US20040087548A1 - Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function - Google Patents

Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function Download PDF

Info

Publication number
US20040087548A1
US20040087548A1 US10/075,870 US7587002A US2004087548A1 US 20040087548 A1 US20040087548 A1 US 20040087548A1 US 7587002 A US7587002 A US 7587002A US 2004087548 A1 US2004087548 A1 US 2004087548A1
Authority
US
United States
Prior art keywords
isoindole
dione
tetrahydro
substituted
methano
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/075,870
Other languages
English (en)
Inventor
Mark Salvati
Ricardo Attar
Marco Gottardis
James Balog
Dacia Pickering
Rogelio Martinez
Chongping Sun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to US10/075,870 priority Critical patent/US20040087548A1/en
Assigned to BRISTOL-MYERS SQUIBB COMPANY reassignment BRISTOL-MYERS SQUIBB COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOTTARDIS, MARCO M., ATTAR, RICARDO M., BALOG, JAMES AARON, MARTINEZ, ROGELIO L., PICKERING, DACIA A., SALVATI, MARK E., SUN, CHONGQING
Publication of US20040087548A1 publication Critical patent/US20040087548A1/en
Priority to US11/311,731 priority patent/US7655688B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to fused cyclic compounds, to methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer, and to pharmaceutical compositions containing such compounds.
  • Nuclear hormone receptors constitute a large super-family of ligand-dependent and sequence-specific transcription factors. Members of this family influence transcription either directly, through specific binding to the promoter target genes (Evans, in Science 240: 889-895 (1988)), or indirectly, via protein-protein interactions with other transcription factors (Jonat et al., Cell 62: 1189-1204 (1990), Schuele et al., Cell 62: 1217-1226 (1990), and Yang-Yen et al., Cell 62: 1205-1215 (1990)).
  • the nuclear hormone receptor super-family (also known in the art as the “steroid/thyroid hormone receptor super-family”) includes receptors for a variety of hydrophobic ligands, including cortisol, aldosterone, estrogen, progesterone, testosterone, vitamine D3, thyroid hormone and retinoic acid (Evans, 1988, supra).
  • the super-family contains a number of proteins that have no known ligands, termed orphan nuclear hormone receptors (Mangelsdorf et al., Cell 83: 835-839 (1995), O'Malley et al., Mol. Endocrinol. 10: 1293 (1996), Enmark et al., Mol. Endocrinol.
  • the conventional nuclear hormone receptors are generally transactivators in the presence of ligand, and can either be active repressors or transcriptionally inert in the absence of ligand. Some of the orphan receptors behave as if they are transcriptionally inert in the absence of ligand. Others, however, behave as either constitutive activators or repressors. These orphan nuclear hormone receptors are either under the control of ubiquitous ligands that have not been identified, or do not need to bind ligand to exert these activities.
  • the nuclear hormone receptors have a modular structure, being comprised of three distinct domains: an N-terminal domain of variable size containing a transcriptional activation function AF-1, a highly conserved DNA binding domain and a moderately conserved ligand-binding domain.
  • the ligand-binding domain is not only responsible for binding the specific ligand but also contains a transcriptional activation function called AF-2 and a dimerisation domain (Wurtz et al., Nature Struc. Biol. 3, 87-94 (1996), Parker et al., Nature Struc. Biol. 3, 113-115 (1996) and Kumar et al., Steroids 64, 310-319 (1999)).
  • SB-NHR's The steroid binding nuclear hormone receptors (SB-NHR's) comprise a sub-family of nuclear hormone receptors. These receptors are related in that they share a stronger sequence homology to one another, particularly in the ligand binding domain (LBD), than to the other members of the NHR super-family (Evans, 1988, supra) and they all utilize steroid based ligands.
  • LBD ligand binding domain
  • NHR's are the androgen receptor (AR), the estrogen receptor (ER), the progesterone receptor (PR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the aldosterone receptor (ALDR) and the steroid and xenobiotic receptor (SXR) (Evans et al., WO 99/35246).
  • AR androgen receptor
  • ER estrogen receptor
  • PR progesterone receptor
  • GR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • ADR aldosterone receptor
  • SXR steroid and xenobiotic receptor
  • the natural ligands for each is derived from a common steroid core.
  • examples of some of the steroid based ligands utilized by members of the SB-NHR's include cortisol, aldosterone, estrogen, progesterone, testosterone and dihydrotestosterone. Specificity of a particular steroid based ligand for one SB-NHR versus another is obtained by differential substitution about the steroid core.
  • RU486 is an example of a synthetic agonist of the PR, which is utilized as a birth control agent (Vegeto et al., Cell 69: 703-713 (1992)), and Flutamide is an example of an antagonist of the AR, which is utilized for the treatment of prostate cancer (Neri et al, Endo. 91, 427-437 (1972)).
  • Tamoxifen is an example of a tissues specific modulator of the ER function, that is used in the treatment of breast cancer (Smigel, J. Natl. Cancer Inst. 90, 647-648 (1998)). Tamoxifen can function as an antagonist of the ER in breast tissue while acting as an agonist of the ER in bone (Grese et al., Proc. Natl. Acad. Sci. USA 94, 14105-14110 (1997)). Because of the tissue selective effects seen for Tamoxifen, this agent and agents like it are referred to as “partial-agonist” or partial-antagonist”.
  • non-endogenous ligands for NHR's can be obtained from food sources (Regal et al., Proc. Soc. Exp. Biol. Med. 223, 372-378 (2000) and Hempstock et al., J. Med. Food 2, 267-269 (1999)).
  • the flavanoid phytoestrogens are an example of an unnatural ligand for SB-NHR's that are readily obtained from a food source such as soy (Quella et al., J. Clin. Oncol. 18, 1068-1074 (2000) and Banz et al., J. Med. Food 2, 271-273 (1999)).
  • soy Quella et al., J. Clin. Oncol. 18, 1068-1074 (2000) and Banz et al., J. Med. Food 2, 271-273 (1999)
  • non-natural ligands can be synthetically engineered to serve as modulators of the function of NHR's.
  • engineering of an unnatural ligand can include the identification of a core structure which mimics the natural steroid core system. This can be achieved by random screening against several SB-NHR's or through directed approaches using the available crystal structures of a variety of NHR ligand binding domains (Bourguet et al., Nature 375, 377-382 (1995), Brzozowski, et al., Nature 389, 753-758 (1997), Shiau et al., Cell 95, 927-937 (1998) and Tanenbaum et al., Proc. Natl.
  • Differential substitution about such a steroid mimic core can provide agents with selectivity for one receptor versus another. In addition, such modifications can be employed to obtain agents with agonist or antagonist activity for a particular SB-NHR. Differential substitution about the steroid mimic core can result in the formation of a series of high affinity agonists and antagonists with specificity for, for example, ER versus PR versus AR versus GR versus MR. Such an approach of differential substitution has been reported, for example, for quinoline based modulators of steroid NHR in J. Med. Chem., 41, 623 (1999); WO 9749709; U.S. Pat. No. 5,696,133; U.S. Pat.
  • the compounds of the present invention comprise a core which serves as a steroid mimic, and are useful as modulators of the function of steroid binding nuclear hormone receptors, as well as other NHR as described following.
  • the present invention provides fused cyclic compounds of the following formula I and salts thereof, which compounds are especially useful as modulators of nuclear hormone receptor function:
  • G is a cycloalkenyl, aryl or heterocyclo (e.g., heteroaryl) group, where said group is mono- or polycyclic, and which is optionally substituted at one or more positions, preferably with hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, halo, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclo or substituted heterocyclo, arylalkyl or substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl, CN, R 1 OC ⁇ O, R 1 C ⁇ O—O—, R 1 C ⁇ O, R 1 C ⁇ S, R 1 HNC ⁇ O, R 1 R 2 NC ⁇ O, HOCR 3 R 3′ , nitro, R 1 OCH 2 ,
  • Z 1 is O, S, NH, or NR 6 ;
  • Z 2 is O, S, NH, or NR 6 ;
  • W is CR 7 R 7′ —CR 7 R 7′ , CR 8 ⁇ CR 8′ , CR 7 R 7′ —C ⁇ O, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl;
  • a 1 is CR 7 or N
  • a 2 is CR 7 or N; or alternatively
  • W is CR 7 R 7′ —CR 7 R 7′ , CR 8 ⁇ CR 8′ , CR 7 R 7′ —C ⁇ O ′ , cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, or aryl or substituted aryl;
  • a 1 is CR 7 R 7′ or NR 7 ;
  • a 2 is CR 7 R 7′ or NR 7 ; or alternatively
  • a 1 , A 2 and W together are —NR 7 —N ⁇ N—;
  • Q 1 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl, arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl, aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or substituted heterocyclo (e.g., substituted heteroaryl), halo, CN, R 1 OC ⁇ O, R 4 C ⁇ O, R 5 R 6 NC ⁇ O, HOCR 7 R 7′ , nitro, R 1 OCH 2 , R 1 O, NH 2 , C ⁇ OSR 1 , SO 2 R 1 or NR 4 R 5 ;
  • Q 2 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl, arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl, aryl or substituted aryl, heterocyclo (e.g., heteroaryl) or substituted heterocyclo (e.g., substituted heteroaryl), halo, CN, R 1 OC ⁇ O, R 4 C ⁇ O, R 5 R 6 NC ⁇ O, HOCR 7 R 7′ , nitro, R 1 OCH 2 , R 1 O, NH 2 , C ⁇ OSR 1 , SO 2 R 1 or NR 4 R 5 ;
  • R 1 and R 1′ are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl;
  • R 2 is alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl;
  • R 3 and R 3′ are each independently H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, CN, hydroxylamine, hydroxamide, alkoxy or substituted alkoxy, amino, NR 1 R 2 , thiol, alkylthio or substituted alkylthio;
  • R 4 is H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R 1 C ⁇ O, R 1 NHC ⁇ O, SO 2 OR 1 , or SO 2 NR 1 R 1′ ;
  • R 5 is alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R 1 C ⁇ O, R 1 NHC ⁇ O, SO 2 R 1 , SO 2 OR 1 , or SO 2 NR 1 R 1′ ;
  • R 6 is alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR 1 , R 1 C ⁇ O, R 1 NHC ⁇ O, SO 2 R 1 , SO 2 OR 1 , or SO 2 NR 1 R 1′ ;
  • R 7 and R 7′ are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, CN, OR 1 , nitro, hydroxylamine, hydroxylamide, amino, NHR 4 , NR 2 R 5 , NOR 1 , thiol, alkylthio or substituted alkylthio, R 1 C ⁇ O, R 1 OC ⁇ O, R 1 C ⁇ O—O—, R 1
  • R 8 and R 8′ are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkyalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, nitro, halo, CN, OR 1 , amino, NHR 4 , NR 2 R 5 , NOR 1 , alkylthio or substituted alkylthio, C ⁇ OSR 1 , R 1 OC ⁇ O, R 1 C ⁇ O, R 1 NHC ⁇ O, R 1 R 1′ NC ⁇ O, SO 2 OR 1
  • the compounds of formula I and salts thereof comprise a core which can serve as a steroid mimic (and do not require the presence of a steroid-type (e.g., cyclopentanoperhydrophenanthrene analog) structure).
  • a steroid-type e.g., cyclopentanoperhydrophenanthrene analog
  • alkyl and alk refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms.
  • exemplary such groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • Substituted alkyl refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include but are not limited to one or more of the following groups: halo (e.g., a single halo substituent or multiple halo substitutents forming, in the latter case, groups such as a perfluoroalkyl group or an alkyl group bearing Cl 3 or CF 3 ), alkoxy, alkylthio, hydroxy, carboxy (i.e., —COOH), alkoxycarbonyl, alkylcarbonyloxy, CN, amino (i.e., —NH 2 ), alkylamino, dialkylamino, carbamoyl or substituted carbomoyl, carbamate or substituted carbamate, urea or substituted urea, amidinyl or substituted amidinyl, thiol (i.e., —SH),
  • groups such as “alkyl”, “aryl” and “heterocycle” can themselves be optionally substituted; for example, “alkyl” in the group “NCH ⁇ OO-alkyl” recited above can be optionally substituted so that both “NHC ⁇ OO-alkyl” and “NHC ⁇ OO-substituted alkyl” are exemplary substitutents.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. “Substituted alkenyl” refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. “Substituted alkynyl” refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. “Substituted cycloalkyl” refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents, and as previously mentioned as preferred aryl substituents in the definition for G.
  • substituents also include spiro-attached or fused cyclic substituents, especially cycloalkenyl or substituted cycloalkenyl.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include but are not limited to nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents, and as previously mentioned as preferred aryl substituents in the definition for G.
  • substituents also include spiro-attached or fused cyclic substituents, especially cycloalkyl or substituted cycloalkyl, or aryl or substituted aryl.
  • alkoxy or “alkylthio” refer to an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
  • substituted alkoxy or “substituted alkylthio” refer to a substituted alkyl group as described above bonded through an oxygen or sulfur linkage, respectively.
  • alkoxycarbonyl refers to an alkoxy group bonded through a carbonyl group.
  • alkylcarbonyl refers to an alkyl group bonded through a carbonyl group.
  • alkylcarbonyloxy refers to an alkylcarbonyl group bonded through an oxygen linkage.
  • arylalkyl refers to aryl, cycloalkyl, cycloalkenylalkyl, “substituted cycloalkenylalkyl”, “heterocycloalkyl” and “substituted heterocycloalkyl” refer to aryl, cycloalkyl, cycloalkenyl and heterocyclo groups bonded through an alkyl group, substituted on the aryl, cycloalkyl, cycloalkenyl or heterocyclo and/or the alkyl group where indicated as “substituted.”
  • aryl refers to cyclic, aromatic hydrocarbon groups which have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). “Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1, 2, 3, 4 or 5 substituents, at any point of attachment.
  • substituents also include fused cyclic substituents, such as heterocyclo or cycloalkenyl, or substituted heterocyclo or cycloalkenyl, groups (e.g., thereby forming a fluoroenyl, tetrahydronapthalenyl, or dihydroindenyl group).
  • fused cyclic substituents such as heterocyclo or cycloalkenyl, or substituted heterocyclo or cycloalkenyl, groups (e.g., thereby forming a fluoroenyl, tetrahydronapthalenyl, or dihydroindenyl group).
  • Carbamoyl refers to the group —CONH— which is bonded on one end to the remainder of the molecule and on the other to hydrogen or an organic moiety (such as alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, alkylcarbonyl, hydroxyl and substituted nitrogen).
  • “Carbamate” refers to the group —O—CO—NH— which is bonded on one end to the remainder of the molecule and on the other to hydrogen or an organic moiety (such as those listed above).
  • “Urea” refers to the group —NH—CO—NH— which is bonded on one end to the remainder of the molecule and on the other to hydrogen or an organic moiety (such as those listed above).
  • “Amidinyl” refers to the group —C( ⁇ NH)(NH 2 ). “Substituted carbamoyl,” “substituted carbamate,” “substituted urea” and “substituted amidinyl” refer to carbamoyl, carbamate, urea or amidinyl groups as described above in which one more of the hydrogen groups are replaced by an organic moiety (such as those listed above).
  • heterocycle refers to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic i.e., “heteroaryl”
  • cyclic groups for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16 membered tricyclic ring systems
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • heteroarylium refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.
  • the heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system.
  • Exemplary monocyclic heterocyclic groups include ethylene oxide, azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl,
  • bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydrobenzodioxinyl, dihydrodioxidobenzo
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • Substituted heterocycle refers to heterocycle, heterocyclic or heterocyclo groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • quaternary nitrogen refers to a tetravalent positively charged nitrogen atom including, for example, the positively charged nitrogen in a tetraalkylammonium group (e.g., tetraethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g., trimethyl-hydroammonium, N-hydropyridinium), the positively charged nitrogen in amine N-oxides (e.g., N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).
  • a tetraalkylammonium group e.g., tetraethylammonium, N-methylpyridinium
  • protonated ammonium species e.g., trimethyl-hydroammonium, N-hydropyridinium
  • halogen or “halo” refer to chlorine, bromine, fluorine or iodine.
  • hydroxylamine and “hydroxylamide” refer to the groups OH—NH— and OH—NH—CO—, respectively.
  • protecting groups for the methods and compounds described herein include, without limitation, those described in standard textbooks, such as Greene, T. W. et al., Protective Groups in Organic Synthesis , Wiley, N.Y. (1991).
  • (CRR)n When a term such as “(CRR)n” is used, it denotes an optionally substituted alkyl chain existing between the two fragments to which it is bonded, the length of which chain is defined by the range described for the term n.
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • Divalent groups such as those in the definition of W (e.g., CR 7 R 7′ —C ⁇ O), may be bonded in either direction to the remainder of the molecule (e.g,
  • Carboxylate anion refers to a negatively charged group —COO — .
  • the compounds of formula I form salts which are also within the scope of this invention.
  • Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions inner salts may be formed and are included within the term “salt(s)” as used herein.
  • Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of formula I which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides,
  • the compounds of formula I which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term “prodrug” as employed herein denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof.
  • Solvates of the compounds of formula I include, for example, hydrates.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form.
  • the definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclo rings.
  • the exo or endo conformation can be preferred for the fused ring system bonded to G—L in formula L.
  • the preferred configuration can be a function of the particular compound and its preferred activity. Separation of configurational isomers can be achieved by any suitable method, such as column chromatography.
  • the compounds of the present invention may be prepared by methods such as those illustrated in the following Schemes I to IV. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Combinatorial techniques may be employed in the preparation of compounds, for example, where the intermediates possess groups suitable for these techniques. See the following which describe other methods which may be employed in the preparation of compounds of the present invention: Li, et al., Eur. J. Org. Chem. 9, 1841-1850 (1998); Li, Y-Q, Synlett. 5, 461-464 (1996); Thiemann, et al., Bull. Chem. Soc. Jpn.
  • a diene of formula II can be reacted with a dienophile of formula III, under conditions readily selected by one skilled in the art (such as by the addition of heat (“ ⁇ ”)), to obtain a compound of formula IV, which is a compound of formula I.
  • An intermediate diene of formula II can be obtained from commercial sources or readily made by one skilled in the art, for example, in accordance with the following literature documents and the references found therein: Hofman et al., J. Agric. Food Chem. 45, 898-906 (1997); Baciocchi et al., J. Chem. Soc., Perkin Trans. 2 8, 821-824 (1975); Wu et al., J.
  • An intermediate dieneophile of formula III can be obtained from commercial sources or readily made by one skilled in the art, for example, in accordance with the following literature references and the references found therein: Deshpande et al., Heterocycles 51, 2159-2162 (1999); Seijas et al., J. Chem. Res., Synop. 7, 420-421 (1999); Langer et al., Eur. J. Org. Chem.
  • compounds of formula I can be obtained by reaction of a primary amine of formula V with a substituted anhydride-like intermediate of formula VI, for example, in a solvent such as acetic acid with or without heating, to yield a compound of formula IV, which is a compound of formula I.
  • Primary amines of formula V can be obtained from commercial sources or readily synthesized by one skilled in the art.
  • Anhydride-like agents of formula VI can be obtained from commercial sources or readily synthesized by one skilled in the art.
  • the documents listed following describe exemplary approaches for the synthesis of intermediates of formula VI as well as synthetic approaches which can be applied to the synthesis of compounds of formula IV (all incorporated herein by reference in their entirety): Kohler, E.
  • Scheme III describes a method for preparing an intermediate compound of formula VI which can be used to synthesize a compound of formula I, as described in Scheme II.
  • a diene of formula II can be reacted with a dieneophile of formula VII to yield the intermediate of formula VI.
  • the methods applied to obtain such a transformation are analogous to those described in Scheme I.
  • Scheme IV describes a method for preparing an intermediate compound of formula VI which can be used to synthesize a compound of formula I, as described in Scheme II.
  • a diene of formula II can be reacted with a dieneophile of formula VIII to yield the intermediate of formula IX.
  • the intermediate of formula IX can be dehydrated to an anhydride-like intermediate of formula VI. Dehydration of the bis-acid intermediate of formula IX to can be achieved by a variety of methods, such as those known to one skilled in the art and described in the following documents and the references embodied therein: Sprague et al., J. Med. Chem. 28, 1580-1590 (1985); and/or Retemi et al., J. Org. Chem. 61, 6296-6301 (1996).
  • a preferred subgenus of the compounds of the present invention includes compounds of the formula I or salts thereof wherein one or more, preferably all, of the following substituents are as defined below:
  • G is a cycloalkenyl, an aryl (preferably phenyl or naphthyl), or heterocyclo (e.g., heteroaryl) group, where said group is mono- or polycyclic, and which is optionally substituted at one or more positions, preferably with hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, halo, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclo or substituted heterocyclo, arylalkyl or substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl, CN, R 1 OC ⁇ O, R 1 C ⁇ O—O—, R 1 C ⁇ O, R 1 C ⁇ S, R 1 HNC ⁇ O, R 1 R 2 NC ⁇ O, HOCR 3 R
  • Z 1 is O or S
  • Z 2 is O or S
  • W is CR 7 R 7′ —CR 7 R 7′ , CR 8 ⁇ CR 8′ , CR 7 R 7′ —C ⁇ O, cycloalkyl or substituted cycloalkyl, or aryl or substituted aryl;
  • a 1 is CR 7 ;
  • a 2 is CR 7 ; or alternatively,
  • W is CR 7 R 7′ —CR 7 R 7′ or CR 8 ⁇ CR 8′ ;
  • a 1 is CR 7 ;
  • a 2 is CR 7 ; or alternatively,
  • a 1 , A 2 and W together are —NR 7 —N ⁇ N—;
  • Q 1 is H, alkyl or substituted alkyl
  • Q 2 is H, alkyl or substituted alky
  • L is a bond, NH or NR 5 .
  • the compounds of the present invention modulate the function of nuclear hormone receptors (NHR), and include compounds which are, for example, agonists, partial agonists, antagonists or partial antagonists of the androgen receptor (AR), the estrogen receptor (ER), the progesterone receptor (PR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the steroid and xenobiotic receptor (SXR), other steroid binding NHR's, the Orphan receptors or other NHR's. Selective modulation of one such NHR relative to others within the NHR family is preferred. “Modulation” includes, for example, activation (e.g., agonist activity) or inhibition (e.g., antagonist activity).
  • NHR-associated condition denotes a condition or disorder which can be treated by modulating the function of a NHR in a subject, wherein treatment comprises prevention, partial alleviation or cure of the condition or disorder. Modulation may occur locally, for example, within certain tissues of the subject, or more extensively throughout a subject being treated for such a condition disorder.
  • the compounds of the present invention are useful for the treatment of a variety of conditions and disorders including, but not limited to, those described following:
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists, or partial antagonists of the estrogen receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the estrogen receptor pathway.
  • Applications of said compounds include but are not limited to: osteoporosis, hot flushes, vaginal dryness, prostate cancer, breast cancer, endometrial cancer, cancers expressing the estrogen receptor such as the aforementioned cancers and others, contraception, pregnancy termination, menopause, amennoreahea, and dysmennoreahea.
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the progesterone receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the progesterone receptor pathway.
  • Applications of said compounds include but are not limited to: breast cancer, other cancers containing the progesterone receptor, endometriosis, cachexia, contraception, menopause, cyclesynchrony, meniginoma, dysmennoreahea, fibroids, pregnancy termination, labor induction and osteoporosis.
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the glucocorticoid receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the glucocorticoid receptor pathway.
  • Applications of said compounds include but are not limited to: inflammatory diseases, autoimmune diseases, prostate cancer, breast cancer, Alzheimer's disease, psychotic disorders, drug dependence, non-insulin dependent Diabetes Mellitus, and as dopamine receptor blocking agents or otherwise as agents for the treatment of dopamine receptor mediated disorders.
  • Glucocorticoid receptor AP-1 (“GR AP-1”) inhibitors can be used as anti-inflammatory and immunosuppressive agents, for example, to treat a wide variety of inflammatory and autoimmune diseases. These diseases include without limitation: rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, prevention of transplant rejection, multiple sclerosis, and psoriasis, among others.
  • GR AP-1 inhibitors of the present invention can be employed together with known GR AP-1 inhibitors, such as the steroid prednisone (which is used to treat the above diseases).
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the mineralocorticoid receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the mineralocorticoid receptor pathway.
  • Applications of said compounds include but are not limited to: drug withdrawal syndrome and inflammatory diseases.
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the aldosterone receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the aldosterone receptor pathway.
  • One application of said compounds includes but is not limited to: congestive heart failure.
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the androgen receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the androgen receptor pathway.
  • Applications of said compounds include but are not limited to: hirsutism, acne, seborrhea, Alzheimer's disease, androgenic alopecia, hypogonadism, hyperpilosity, benign prostate hypertrophia, adenomas and neoplasies of the prostate (such as advanced metastatic prostate cancer), treatment of benign or malignant tumor cells containing the androgen receptor such as is the case for breast, brain, skin, ovarian, bladder, lymphatic, liver and kidney cancers, pancreatic cancers, modulation of VCAM expression and applications therein for the treatment of heart disease, inflammation and immune modulations, modulation of VEGF expression and the applications therein for use as antiangiogenic agents, osteoporosis, suppressing spermatogenesis, lib
  • Compounds of formula I can be applied as (preferably, selective) antagonists of the mutated androgen receptor, for example, found in many tumor lines.
  • mutants are those found in representative prostate tumor cell lines such as LNCap, (T877A mutation, Biophys. Acta, 187, 1052 (1990)), PCa2b, (L701H & T877A mutations, J. Urol., 162, 2192 (1999)) and CWR22, (H874Y mutation, Mol. Endo., 11, 450 (1997)).
  • Applications of said compounds include but are not limited to: adenomas and neoplasies of the prostate, breast cancer and endometrial cancer.
  • Compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the steroid and xenobiotic receptor, preferably selectively to that receptor, in an array of medical conditions which involve modulation of the steroid and xenobiotic receptor pathway.
  • Applications of said compounds include but are not limited to: treatment of disregulation of cholesterol homeostasis, attenuation of metabolism of pharmaceutical agents by co-administration of an agent (compound of the present invention) which modulates the P450 regulator effects of SXR.
  • NHR NHR due to strong sequence homology to other NHR
  • Orphan receptors demonstrate strong sequence homology to other NHR
  • compounds of formula I include those which serve as modulators of the function of the Orphan NHR.
  • Orphan receptors which are modulated by NHR modulators such as compounds within the scope of formula I are exemplified, but not limited to, those listed in Table 1.
  • Exemplary therapeutic applications of modulators of said Orphan receptors are also listed in Table 1, but are not limited to the examples therein.
  • the present invention thus provides methods for the treatment of NHR-associated conditions, comprising the step of administering to a subject in need thereof at least one compound of formula I in an amount effective therefor.
  • Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods (for example, separately, or formulated together as a fixed dose).
  • such other therapeutic agent(s) can be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
  • the present invention also provides pharmaceutical compositions comprising at least one of the compounds of the formula I capable of treating a NHR-associated condition in an amount effective therefor, and a pharmaceutically acceptable carrier (vehicle or diluent).
  • a pharmaceutically acceptable carrier vehicle or diluent.
  • the compositions of the present invention can contain other therapeutic agents as described below, and can be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • the compounds of the present invention are, without limitation as to their mechanism of action, useful in treating any of the conditions or disorders listed or described herein such as inflammatory diseases or cancers, or other proliferate diseases, and in compositions for treating such conditions or disorders.
  • the present compounds have therapeutic utility in the modulation of immune cell activation/proliferation, e.g., as competitive inhibitors of intercellular ligand/receptor binding reactions involving CAMs (Cellular Adhesion Molecules) and Leukointegrins.
  • the present compounds modulate LFA-ICAM 1, and are particularly useful as LFA-ICAM 1 antagonists, and in the treatment of all conditions associated with LFA-ICAM 1 such as immunological disorders.
  • Preferred utilities for the present compounds include, but are not limited to: inflammatory conditions such as those resulting from a response of the non-specific immune system in a mammal (e.g., adult respiratory distress syndrome, shock, oxygen toxicity, multiple organ injury syndrome secondary to septicemia, multiple organ injury syndrome secondary to trauma, reperfusion injury of tissue due to cardiopulmonary bypass, myocardial infarction or use with thrombolysis agents, acute glomerulonephritis, vasculitis, reactive arthritis, dermatosis with acute inflammatory components, stroke, thermal injury, hemodialysis, leukapheresis, ulcerative colitis, necrotizing enterocolitis and granulocyte transfusion associated syndrome) and conditions resulting from a response of the specific immune system in a mammal (e.g., psoriasis, organ/tissue transplant rejection, graft vs.
  • inflammatory conditions such as those resulting from a response of the non-specific immune system in a mammal (e.g., adult
  • the present compounds can be used in treating asthma or as an adjunct to minimize toxicity with cytokine therapy in the treatment of cancers.
  • the present compounds can be employed in the treatment of all diseases currently treatable through steroid therapy.
  • the present compounds may be employed for the treatment of these and other disorders alone or with other immunosuppressive or antiinflammatory agents.
  • a compound of the formula I can be administered prior to the onset of inflammation (so as to suppress an anticipated inflammation) or after the initiation of inflammation.
  • the immunosupressive compound(s) are preferably provided in advance of any inflammatory response or symptom (for example, prior to, at, or shortly after the time of an organ or tissue transplant but in advance of any symptoms or organ rejection).
  • the prophylactic administration of a compound of the formula I prevents or attenuates any subsequent inflammatory response (such as, for example, rejection of a transplanted organ or tissue, etc.)
  • Administration of a compound of the formula I attenuates any actual inflammation (such as, for example, the rejection of a transplanted organ or tissue).
  • the compounds of the formula I can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.
  • the present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the present compounds can also be administered liposomally.
  • compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
  • the compounds of formula I can also be delivered through the oral cavity by sublingual and/or buccal administration.
  • Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
  • Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).
  • Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • maleic anhydride copolymer e.g., Gantrez
  • agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • compositions for nasal aerosol or inhalation administration include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • the effective amount of a compound of the present invention can be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a adult human of from about 1 to 100 (for example, 15) mg/kg of body weight of active compound per day, which can be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to NHR-associated conditions.
  • the compounds of the present invention can be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of NHR-associated conditions.
  • the compounds of the present invention can be administered either alone or in combination with other anti-cancer and cytotoxic agents and treatments useful in the treatment of cancer or other proliferative diseases, for example, where the second drug has the same or different mechanism of action than the present compounds of formula I.
  • Examples of classes of anti-cancer and cytotoxic agents useful in combination with the present compounds include but are not limited to: alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; farnesyl-protein transferase inhibitors; 5 ⁇ reductase inhibitors; inhibitors of 17 ⁇ -hydroxy steroid dehydrogenase type 3; hormonal agents such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, octreotide acetate; microtubule-dis
  • Representative examples of these classes of anti-cancer and cytotoxic agents include but are not limited to mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, etoposide, etoposide phosphate
  • Preferred member of these classes include, but are not limited to, paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, or porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine and leurosine.
  • anticancer and other cytotoxic agents include the following: epothilone derivatives as found in German Patent No. 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253 and WO 00/00485; cyclin dependent kinase inhibitors as found in WO 99/24416 (see also U.S.
  • the combinations of the present invention can also be formulated or co-administered with other therapeutic agents that are selected for their particular usefulness in administering therapies associated with the aforementioned conditions.
  • the compounds of the invention may be formulated with agents to prevent nausea, hypersensitivity and gastric irritation, such as antiemetics, and H 1 and H 2 antihistaminics.
  • the compounds of this invention are most preferably used alone or in combination with anti-cancer treatments such as radiation therapy and/or with cytostatic and/or cytotoxic agents, such as, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; inhibitors of farnesyl protein transferase, such as those described in U.S. Pat. No.
  • anti-cancer treatments such as radiation therapy and/or with cytostatic and/or cytotoxic agents, such as, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; inhibitors of farnesyl protein transferase, such as those described in U.S. Pat. No.
  • topoisomerase II inhibitors such as etoposide
  • topoisomerase I inhibitors such as CPT-11 or topotecan
  • tubulin stabilizing agents such as paclitaxel, docetaxel, other taxanes, or epothilones
  • hormonal agents such as tamoxifen
  • thymidilate synthase inhibitors such as 5-fluorouracil
  • antimetabolites such as methoxtrexate
  • antiangiogenic agents such as angiostatin, ZD6474, ZD6126 and comberstatin A2
  • kinase inhibitors such as her2 specific antibodies, Iressa and CDK inhibitors
  • histone deacetylase inhibitors such as CI-994 and MS-27-275.
  • Such compounds may also be combined with agents which suppress the production of circulating testosterone such as LHRH agonists or antagonists or with surgical castration.
  • known therapies for advanced metastatic prostate cancer include “complete androgen ablation therapy” wherein tumor growth is inhibited by controlling the supply of androgen to the prostate tissues via chemical castration (castration serves to inhibit the production of circulating testosterone (T) and dihydrotestosterone (DHT)) followed by the administration of androgen receptor (AR) antagonists (which inhibit the function T/DHT derived from the conversion of circulating androgen precursors to T/DHT by the prostate tissue).
  • the compounds of the present invention can be employed as AR antagonists in complete ablation therapy, alone or in combination with other AR antagonists such as Flutamide, Casodex, Nilutamide, or Cyproterone acetate.
  • the compounds of the present invention may be employed adjuvant to surgery.
  • Another application of the present compounds is in combination with antibody therapy such as but not limited to antibody therapy against PSCA.
  • An additional application is in concert with vaccine/immune modulating agents for the treatment of cancer.
  • the following assays can be employed in ascertaining the activity of a compound as a NHR modulator. Preferred are those compounds with an activity greater than 20 ⁇ m for binding or transactivation in any of these assays.
  • Various compounds of the present invention were determined to have AR modulator activity utilizing the transactivation assay, and standard AR binding assays as described following.
  • transactivation assays of a transfected reporter construct and using the endogenous androgen receptor of the host cells.
  • the transactivation assay provides a method for identifying functional agonists and partial agonists that mimic, or antagonists that inhibit, the effect of native hormones, in this case, dihydrotestosterone (DHT).
  • DHT dihydrotestosterone
  • This assay can be used to predict in vivo activity as there is a good correlation in both series of data. See, e.g. T. Berger et al., J. Steroid Biochem. Molec. Biol. 773 (1992), the disclosure of which is herein incorporated by reference.
  • reporter plasmid is introduced by transfection (a procedure to induce cells to take foreign genes) into the respective cells.
  • This reporter plasmid comprising the cDNA for a reporter protein, such as secreted alkaline phosphatase (SEAP), controlled by prostate specific antigen (PSA) upstream sequences containing androgen response elements (AREs).
  • SEAP secreted alkaline phosphatase
  • PSA prostate specific antigen
  • AREs upstream sequences containing androgen response elements
  • This reporter plasmid functions as a reporter for the transcription-modulating activity of the AR.
  • the reporter acts as a surrogate for the products (mRNA then protein) normally expressed by a gene under control of the AR and its native hormone.
  • the transactivation assay is carried out in the presence of constant concentration of the natural AR hormone (DHT) known to induce a defined reporter signal.
  • DHT natural AR hormone
  • Increasing concentrations of a suspected antagonist will decrease the reporter signal (e.g., SEAP production).
  • exposing the transfected cells to increasing concentrations of a suspected agonist will increase the production of the reporter signal.
  • LNCaP and MDA 453 cells were obtained from the American Type Culture Collection (Rockville, Md.), and maintained in RPMI 1640 or DMEM medium supplemented with 10% fetal bovine serum (FBS; Gibco) respectively.
  • the respective cells were transiently transfected by electroporation according to the optimized procedure described by Heiser, 130 Methods Mol. Biol., 117 (2000), with the pSEAP2/PSA540/Enhancer reporter plasmid.
  • the reporter plasmid was constructed as follows: commercial human placental genomic DNA was used to generate by Polymerase Cycle Reaction (PCR) a fragment containing the BglII site (position 5284) and the Hind III site at position 5831 of the human prostate specific antigen promoter (Accession # U37672), Schuur, et al., J. Biol. Chem., 271 (12): 7043-51 (1996). This fragment was subcloned into the pSEAP2/basic (Clontech) previously digested with BglII and HindIII to generate the pSEAP2/PSA540 construct.
  • PCR Polymerase Cycle Reaction
  • Each cell suspension was distributed into two Gene Pulser Cuvetts (Bio-Rad) which then received 8 ⁇ g of the reporter construct, and electoporated using a Bio-Rad Gene Pulser at 210 volts and 960 ⁇ Faraday. Following the transfections the cells were washed and incubated with media containing charcoal stripped fetal bovine serum in the absence (blank) or presence (control) of 1 nM dihydrotestosterone (DHT; Sigma Chemical) and in the presence or absence of the standard anti-androgen bicalutamide or compounds of the present invention in concentrations ranging from 10-10 to 10-5 M (sample). Duplicates were used for each sample.
  • the compound dilutions were performed on a Biomek 2000 laboratory workstation. After 48 hours, a fraction of the supernatant was assayed for SEAP activity using the Phospha-Light Chemiluminescent Reporter Gene Assay System (Tropix, Inc). Viability of the remaining cells was determined using the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay (MTS Assay, Promega).
  • a mix of a tetrazolium compound (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS) and an electron coupling reagent (phenazine methosulfate; PMS) are added to the cells.
  • MTS Olet's reagent
  • PMS phenazine methosulfate
  • the quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of living cells in culture. For each replicate the SEAP reading was normalized by the Abs490 value derived from the MTS assay. For the antagonist mode, the % Inhibition was calculated as:
  • the reporter plasmid utilized was comprised of the cDNA for the reporter SEAP protein, as described for the AR specific transactivation assay. Expression of the reporter SEAP protein was controlled by the mouse mammary tumor virus long terminal repeat (MMTV LTR) sequences that contains three hormone response elements (HREs) that can be regulated by both GR and PR see, e.g. G. Chalepakis et al., Cell, 53(3), 371 (1988). This plasmid was transfected into A549 cells, which expresses endogenous GR, to obtain a GR specific transactivation assay.
  • MMTV LTR mouse mammary tumor virus long terminal repeat
  • A549 cells were obtained from the American Type Culture Collection (Rockville, Md.), and maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS; Gibco). Determination of the GR specific antagonist activity of the compounds of the present invention was identical to that described for the AR specific transactivation assay, except that the DHT was replaced with 5 nM dexamethasone (Sigma Chemicals), a specific agonist for GR. Determination of the GR specific agonist activity of the compounds of the present invention was performed as described for the AR transactivation assay, wherein one measures the activation of the GR specific reporter system by the addition of a test compound, in the absence of a known GR specific agonists ligand.
  • the reporter plasmid utilized was comprised of the cDNA for the reporter SEAP protein, as described for the AR specific transactivation assay. Expression of the reporter SEAP protein was controlled by the mouse mammary tumor virus long terminal repeat (MMTV LTR) sequences that contains three hormone response elements (HREs) that can be regulated by both GR and PR. This plasmid was transfected into T47D, which expresses endogenous PR, to obtain a PR specific transactivation assay. T47D cells were obtained from the American Type Culture Collection (Rockville, Md.), and maintained in DMEM medium supplemented with 10% fetal bovine serum (FBS; Gibco).
  • FBS fetal bovine serum
  • Determination of the PR specific antagonist activity of the compounds of the present invention was identical to that described for the AR specific transactivation assay, except that the DHT was replaced with 1 nM Promegastone (NEN), a specific agonist for PR. Determination of the PR specific agonist activity of the compounds of the present invention was performed as described for the AR transactivation assay, wherein one measures the activation of the PR specific reporter system by the addition of a test compound, in the absence of a known PR specific agonists ligand.
  • human LNCaP cells T877A mutant AR or MDA 453 (wild type AR) in 96-well microtiter plates containing RPMI 1640 or DMEM supplemented with 10% charcoal stripped CA-FBS (Cocaleco Biologicals) respectively, were incubated at 37° C. to remove any endogenous ligand that might be complexed with the receptor in the cells. After 48 hours, either a saturation analysis to determine the K d for tritiated dihydrotestosterone, [ 3 H]-DHT, or a competitive binding assay to evaluate the ability of test compounds to compete with [ 3 H]-DHT were performed.
  • media RPMI 1640 or DMEM ⁇ 0.2% CA-FBS
  • [ 3 H]-DHT in concentrations ranging from 0.1 nM to 16 nM
  • an aliquot of the total binding media at each concentration of [ 3 H]-DHT was removed to estimate the amount of free [ 3 H]-DHT.
  • test compounds media containing 1 nM [ 3 H]-DHT and compounds of the invention (“test compounds”) in concentrations ranging from 10 ⁇ 10 to 10 ⁇ 5 M were added to the cells. Two replicates were used for each sample. After 4 hours at 37° C., cells were washed, harvested and counted as described above. The data was plotted as the amount of [ 3 H]-DHT (% of control in the absence of test compound) remaining over the range of the dose response curve for a given compound. The concentration of test compound that inhibited 50% of the amount of [ 3 H]-DHT bound in the absence of competing ligand was quantified (IC 50 ) after log-logit transformation.
  • K I IC 50 ( 1 + ( 3 ⁇ H - DHT ) / K d ⁇ ⁇ for ⁇ 3 ⁇ H - DHT .
  • IC 50 values were determined.
  • the IC 50 is defined as the concentration of competing ligand needed to reduce specific binding by 50%.
  • the K d s for [ 3 H]-DHT for MDA 453 and LNCaP were 0.7 and 0.2 nM respectively.
  • test compounds were tested (“test compounds”) on the proliferation of human prostate cancer cell lines.
  • MDA PCa2b cells a cell line derived from the metastasis of a patient that failed castration, Navone et al., Clin. Cancer Res., 3, 2493-500 (1997), were incubated with or without the test compounds for 72 hours and the amount of [ 3 H]-thymidine incorporated into DNA was quantified as a way to assess number of cells and therefore proliferation.
  • the MDA PCa2b cell line was maintained in BRFF-HPC1 media (Biological Research Faculty & Facility Inc., MD) supplemented with 10% FBS.
  • cells were plated in Biocoated 96-well microplates and incubated at 37° C. in 10% FBS (charcoal-stripped)/BRFF-BMZERO (without androgens). After 24 hours, the cells were treated in the absence (blank) or presence of 1 nM DHT (control) or with test compounds (sample) of the present invention in concentrations ranging from 10 ⁇ 10 to 10 ⁇ 5 M. Duplicates were used for each sample. The compound dilutions were performed on a Biomek 2000 laboratory work station. Seventy two hours later 0.44 uCi.
  • the first assay uses a cell line, Stable 1 (clone #72), which stably expresses the full length rat androgen receptor but requires the transient transfection of an enhancer/reporter. This cell line was derived from C2C12 mouse moyoblast cells.
  • the second assay uses a cell line, Stable 2 (clone #133), derived from Stable 1 which stably expresses both rAR and the enhancer/luciferase reporter.
  • the enhancer/reporter construct used in this system is pGL3/2XDR-1/luciferase.
  • 2XDR-1 was reported to be an AR specific response element in CV-1 cells, Brown et. al. The Journal of Biological Chemisty 272, 8227-8235, (1997). It was developed by random mutagenesis of an AR/GR consensus enhancer sequence.
  • Stable 1 cells are plated in 96 well format at 6,000 cells/well in high glucose DMEM without phenol red (Gibco BRL, Cat. No.: 21063-029) containing 10% charcoal and dextran treated FBS (HyClone Cat. No.: SH30068.02), 50 mM HEPES Buffer (Gibco BRL, Cat. No.: 15630-080), 1 ⁇ MEM Na Pyruvate (Gibco BRL, Cat. No.: 11360-070), 0.5 ⁇ Antibiotic-Antimycotic, and 800 ⁇ g/ml Geneticin (Gibco BRL, Cat. No.: 10131-035).
  • LipofectAMINE reagent is diluted with 5 ⁇ l/well Opti-MEM.
  • the DNA mixture is then combined with the LipofectAMINE mixture and incubated for an additional 15 minutes at room temperature. During this time, the media from the cells is removed and replaced with 60 ⁇ l/well of Opti-MEM. To this is added 10 ⁇ l/well of the DNA/LipofectAMINE transfection mixture. The cells are incubated for 4 hours.
  • Stable 2 cells are plated in 96 well format at 6,000 cells/well in high glucose DMEM without phenol red (Gibco BRL, Cat. No.: 21063-029) containing 10% charcoal and dextran treated FBS (HyClone Cat. No.: SH30068.02), 50 mM HEPES Buffer (Gibco BRL, Cat. No.: 15630-080), 1 ⁇ MEM Na Pyruvate (Gibco BRL, Cat. No.: 11360-070), 0.5 ⁇ Antibiotic-Antimycotic, 800 ⁇ g/ml Geneticin (Gibco BRL, Cat. No.: 10131-035) and 800 ⁇ g/ml Hygromycin D (Gibco BRL, Cat. No.: 10687-010).
  • test compounds The ability of compounds of the present invention (“test compounds”) to modulate the function of the AR was determined by testing said compounds in a proliferation assay using the androgen responsive murine breast cell line derived from the Shionogi tumor, Hiraoka et al., Cancer Res., 47, 6560-6564 (1987).
  • Stable AR dependent clones of the parental Shionogi line were established by passing tumor fragments under the general procedures originally described in Tetuo, et. al., Cancer Research 25, 1168-1175 (1965). From the above procedure, one stable line, SC114, was isolated, characterized and utilized for the testing of example compounds.
  • SC114 cells were incubated with or without the test compounds for 72 hours and the amount of [3H]-thymidine incorporated into DNA was quantified as a surrogate endpoint to assess the number of cells and therefore the proliferation rate as described in Suzuki et. al., J. Steroid Biochem. Mol. Biol. 37, 559-567 (1990).
  • the SC114 cell line was maintained in MEM containing 10 ⁇ 8 M testosterone and 2% DCC-treated FCS.
  • cells were plated in 96-well microplates in the maintenance media and incubated at 37° C.
  • the medium was changed to serum free medium [Ham's F-12:MEM (1;1, v/v) containing 0.1% BSA] with (antagonist mode) or without (agonist mode) 10 ⁇ 8 M testosterone and the test compounds of the present invention in concentrations ranging from 10 ⁇ 10 to 10 ⁇ 5 M.
  • Duplicates were used for each sample. The compound dilutions were performed on a Biomek 2000 laboratory work station. Seventy two hours later 0.44 uCi of [3H]-Thymidine (Amersham) was added per well and incubated for another 2 hr followed by tripsinization, and harvesting of the cells onto GF/B filters. Micro-scint PS were added to the filters before counting them on a Beckman TopCount.
  • the AP-1 assay is a cell based luciferase reporter assay.
  • A549 cells which contain endogenous glucocorticoid receptor, were stably transfected with an AP-1 DNA binding site attached to the luciferase gene. Cells are then grown in RPMI+10% fetal calf serum (charcoal-treated)+Penicillin/Streptomycin with 0.5mg/ml geneticin. Cells are plated the day before the assay at approximately 40000 cells/well. On assay day, the media is removed by aspiration and 20 ⁇ l assay buffer (RPMI without phenol red+10% FCS (charcoal-treated)+Pen/Strep) is added to each well.
  • test compounds the compounds of the present invention
  • dexamethasome 100 nM in DMSO, positive control
  • the plates are then pre-incubated for 15 minutes at 37° C., followed by stimulation of the cells with 10 ng/ml PMA.
  • the plates are then incubated for 7 hrs at 37° C. after which 40 ⁇ l luciferase substrate reagent is added to each well.
  • Activity is measured by analysis in a luminometer as compared to control experiments treated with buffer or dexamethasome.
  • Activity is designated as % inhibition of the reporter system as compared to the buffer control with 10 ng/ml PMA alone.
  • the control, dexamethasone, at a concentration of ⁇ 10 ⁇ M typically suppresses activity by 65%.
  • Test compounds which demonstrate an inhibition of PMA induction of 50% or greater at a concentration of test compound of ⁇ 10 ⁇ M are deemed active.
  • T serum testosterone
  • LH pituitary luteinizing hormone
  • FSH follicle stimulating hormone
  • Adrenal androgens also contribute about 20% of total DHT in the rat prostate, compared to 40% of that in 65-year-old men. F. Labrie et al. Clin. Invest. Med., 16, 475-492 (1993). However, this is not a major pathway, since in both animals and humans, castration leads to almost complete involution of the prostate and seminal vesicles without concomitant adrenalectomy. Therefore, under normal conditions, the adrenals do not support significant growth of prostate tissues. M. C. Luke and D. S. Coffey, “ The Physiology of Reproduction ” ed. By E. Knobil and J. D. Neill, 1, 1435-1487 (1994). Since the male sex organs are the tissues most responsive to modulation of the androgen activity, this model is used to determine the androgen dependent growth of the sex accessory organs in immature castrated rats.
  • Testosterone Propionate (TP) (3 mg/rat/day, subcutaneous)
  • TP plus Casodex administered p.o. in PEGTW, QD
  • a recognized antiandrogen as a reference compound.
  • test compound a compound of the present invention was administered (p.o. in PEGTW, QD) with TP (s.c. as administered in group 2) in a range of doses.
  • test compound a compound of the present invention was administered alone (p.o. in PEGTW, QD) in a range of doses.
  • the gain and loss of sexual organ weight reflect the changes of the cell number (DNA content) and cell mass (protein content), depending upon the serum androgen concentration. See Y. Okuda et al., J. Urol., 145, 188-191 (1991), the disclosure of which is herein incorporated by reference. Therefore, measurement of organ wet weight is sufficient to indicate the bioactivity of androgens and androgen antagonist. In immature castrated rats, replacement of exogenous androgens increases seminal vesicles (SV) and the ventral prostate (VP) in a dose dependent manner.
  • SV seminal vesicles
  • VP ventral prostate
  • the maximum increase in organ weight was 4 to 5-fold when dosing 3 mg/rat/day of testosterone (T) or 1 mg/rat/day of testosterone propionate (TP) for 3 days.
  • the EC 50 of T and TP were about 1 mg and 0.03 mg, respectively.
  • the increase in the weight of the VP and SV also correlated with the increase in the serum T and DHT concentration.
  • administration of T showed 5-times higher serum concentrations of T and DHT at 2 hours after subcutaneous injection than that of TP, thereafter, these high levels declined very rapidly.
  • the serum concentrations of T and DHT in TP-treated animals were fairly consistent during the 24 hours, and therefore, TP showed about 10-30-fold higher potency than free T.
  • a known AR antagonist (Casodex) was also administered simultaneously with 0.1 mg of TP (ED 80 ), inhibiting the testosterone-mediated increase in the weights of the VP and SV in a dose dependent manner.
  • the antagonist effects were similar when dosing orally or subcutaneously.
  • Compounds of the invention also exhibited AR antagonist activity by suppressing the testosterone-mediated increase in the weights of VP and SV.
  • the basis of this assay lies in the well-defined action of androgenic agents on the maintenance and growth of muscle tissues and sexual accessory organs in animals and man. Androgenic steroids, such as testosterone (T), have been well characterized for their ability to maintain muscle mass. Treatment of animals or humans after castrations with an exogenous source of T results in a reversal of muscular atrophy. The effects of T on muscular atrophy in the rat levator ani muscle have been well characterized, M. Masuoka et al., “Constant cell population in normal, testosterone deprived and testosterone stimulated levator ani muscles” Am. J. Anat. 119, 263 (1966); Z.
  • Castration results in rapid involution and atrophy of the prostate and seminal vesicles. This effect can be reversed by exogenous addition of androgens. Since both the levator ani muscle and the male sex organs are the tissues most responsive to the effects of androgenic agents, this model is used to determine the androgen dependent reversal of atrophy in the levator ani muscle and the sex accessory organs in immature castrated rats.
  • Sexually mature rats 200-250 g, 6-8 weeks-old, Sprague-Dawley, Harlan
  • the rats were divided into groups and treated daily for 7 to 14 days with one of the following:
  • Testosterone Propionate (TP) (3 mg/rat/day, subcutaneous)
  • TP plus Casodex administered p.o. in PEGTW, QD
  • a recognized antiandrogen as a reference compound.
  • test compound a compound of the present invention was administered (p.o. in PEGTW, QD) with TP (s.c. as administered in group 2) in a range of doses.
  • test compound a compound of the present invention was administered alone (p.o. in PEGTW, QD) in a range of doses.
  • the gain and loss of sexual organ weight reflect the changes of the cell number (DNA content) and cell mass (protein content), depending upon the serum androgen concentration. See Y. Okuda et al., J. Urol., 145, 188-191 (1991), the disclosure of which is herein incorporated by reference. Therefore, measurement of organ wet weight is sufficient to indicate the bioactivity of androgens and androgen antagonist. In immature castrated rats, replacement of exogenous androgens increases levator ani, seminal vesicles (SV) and prostate in a dose dependent manner.
  • SV seminal vesicles
  • the maximum increase in organ weight was 4 to 5-fold when dosing 3 mg/rat/day of testosterone (T) or 1 mg/rat/day of testosterone propionate (TP) for 3 days.
  • the EC 50 of T and TP were about 1 mg and 0.03 mg, respectively.
  • the increase in the weight of the VP and SV also correlated with the increase in the serum T and DHT concentration.
  • administration of T showed 5-times higher serum concentrations of T and DHT at 2 hours after subcutaneous injection than that of TP, thereafter, these high levels declined very rapidly.
  • the serum concentrations of T and DHT in TP-treated animals were fairly consistent during the 24 hours, and therefore, TP showed about 10-30-fold higher potency than free T.
  • MDA-PCa-2b human prostate tumors were maintained in Balb/c nu/nu nude mice. Tumors were propagated as subcutaneous transplants in adult male nude mice (4-6 weeks old) using tumor fragments obtained from donor mice. Tumor passage occurred every 5-6 weeks.
  • Tumor response was determined by measurement of tumors with a caliper twice a week, until the tumors reach a predetermined “target” size of 0.5 gm.
  • Tumor response end-point was expressed in terms of tumor growth inhibition (%T/C), defined as the ratio of median tumor weights of the treated tumors (T) to that of the control group (C).
  • TVDT Median time (days) for control tumors to reach target size ⁇ Median time (days) for control tumors to reach half the target size s
  • Log cell kill (T ⁇ C) ⁇ (3.32 ⁇ TVDT).
  • Dunning R3327H prostate tumor is a spontaneously derived, well differentiated androgen responsive adenocarcinoma of the prostate (Smolev J K, Heston W D, Scott W W, and Coffey D S, Cancer Treat Rep. 61, 273-287 (1977)).
  • the growth of the R3327H subline has been selected for its highly androgen-dependent and reproducible growth in intact male rats. Therefore, this model and other sublines of this tumor have been widely used to evaluate in vivo antitumor activities of antiandrogens such as flutamide and bacilutamide/Casodex (Maucher A., and von Angerer, J. Cancer Res. Clin.
  • the Dunning tumor pieces (about 4 ⁇ 4 mm) are transplanted subcutaneously to the flank of mature male Copenhagen rats (6-7 weeks old, Harlan-Sprague Dawley, Indianapolis, Md.). About 6 weeks after the implantation, the animals with tumors of measurable size (about 80-120 mm 2 ) are randomized into treatment groups (8-10 rats/group) and the treatments are initiated. One group of the rats are castrated to serve as the negative control of tumor growth. Animals are treated daily with compounds of the current invention, standard antiandrogens such as bacilutamide or vehicle (control) for an average of 10 to 14 weeks.
  • standard antiandrogens such as bacilutamide or vehicle (control) for an average of 10 to 14 weeks.
  • Test compounds are dissolved in a vehicle of (2.5 ml/kg of body weight) 10% polyethylene glycol and 0.05% Tween-80 in 1% carboxymethyl cellulose, PEG/CMC, (Sigma, St Louis, Mo.). Typical therapeutic experiments would include three groups of three escalating doses for each standard or test compound (in a range of 300-3 mg/kg).
  • Tumors in the vehicle (control) group reach a size of 1500 to 2500 mm 3 , whereas the castrated animal group typically shows tumor stasis over the 14 weeks of observation.
  • Animals treated orally with 20 mg/kg of bicalutamide or flutamide would be expected to show a 40% reduction in tumor volumes compared to control after 14 weeks of treatment.
  • Statistical differences between treatment groups and control are evaluated using multiple ANOVA analysis followed by one tail non-parametric Student t test.
  • the male sexual accessory organs such as the prostate and seminal vesicles, play an important role in reproductive function. These glands are stimulated to grow and are maintained in size and secretory function by the continued presence of serum testosterone (T), which is the major serum androgen (>95%) produced by the Leydig cells in the testis under the control of the pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH). Testosterone is converted to the more active form, dihydrotestosterone, (DHT), within the prostate by 5 ⁇ -reductase. Adrenal androgens also contribute about 20% of total DHT in the rat prostate, compared to 40% of that in 65-year-old men. F.
  • T serum testosterone
  • LH pituitary luteinizing hormone
  • FSH follicle stimulating hormone
  • DHT dihydrotestosterone
  • Testosterone production in the Leydig cells of the testis is controlled by the level of circulating LH released from the pituitary gland. LH levels are themselves controlled by the level of LHRH produced in the hypothalmic region. Testosterone levels in the blood serve to inhibit the secretion of LHRH and subsequently reduce levels of LH and ultimately the levels of circulating testosterone levels.
  • test compounds By measuring blood levels of LH as they are effected by compounds of the present invention (“test compounds”), it is possible to determine the level of agonist or antagonist activity of said compounds at the hypothalamic axis of this endocrine cycle.
  • Control vehicle p.o., PEGTW, QD
  • Rat luteinizing hormone is quantitatively determined with the Biotrak [125 I] kit (Amersham Pharmacia Biotek), following the manufacturer directions. The assay is based on the competition by the LH present in the serum of the binding of [ 125 I] rLH to an Amerlex-M bead/antibody suspension. The radioactivity that remains after incubation with the serum and subsequent washes is extrapolated into a standard curve to obtain a reading in ng/ml.
  • the gain and loss of sexual organ and levator ani weight reflect the changes of the cell number (DNA content) and cell mass (protein content), depending upon the serum androgen concentration, see Y. Okuda et al., J. Urol., 145, 188-191 (1991), the disclosure of which in herein incorporated by reference. Therefore, measurement of organ wet weight is sufficient to indicate the bioactivity of androgens and androgen antagonist.
  • active agonist agents will have no effect or will increase the weight of one or more of the androgen responsive organs (levator ani, prostate, seminal vessicle) and will have no effect or a suppressive effect on LH secretion.
  • Compounds with antagonist activity will decrease the weight of one or more of the androgen responsive organs (levator ani, prostate, seminal vesicle) and will have no effect or a reduced suppressive effect on LH secretion.
  • CWR22 human prostate tumors were maintained in Balb/c nu/nu nude mice. Tumors were propagated as subcutaneous transplants in adult male nude mice (4-6 weeks old) using tumor fragments obtained from donor mice. Tumor passage occurred every 5-6 weeks.
  • Tumor response was determined by measurement of tumors with a caliper twice a week, until the tumors reach a predetermined “target” size of 0.5 gm.
  • Tumor response end-point was expressed in terms of tumor growth inhibition (%T/C), defined as the ratio of median tumor weights of the treated tumors (T) to that of the control group (C).
  • TFA trifluoroacetic acid
  • TMSOTf trimethylsilyl trifluoromethane sulfonate
  • HMPA hexamethylphosphoramide
  • Lawesson's Reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
  • Freshyl cracked cyclopentadiene monomer of cyclopentadiene generated by Diels-Alder dimer product
  • AIBN 2,2′-azobis(2-methylpropionitrile)
  • Compound 3A was made in accordance with the procedure described oin Norman et. al., U.S. Pat. No. 3,995,099. cis-5-Norbornene-endo-2,3b icarboxylic anhydride (4 g) was heated for 4 hours at 220 ° C. The resus ing solid was recrystallized 4 ⁇ from benzene to give 0.63 g of compound 3A (>99:1 exo by 1 H NMR) as light brown crystals.
  • Cis-1,2,3-propenetricarboxylic acid anhydride (5.00 g, 32.1 mmol) was suspended in dichloroethane (30 mL) and freshly cracked cyclopentadiene (4.23 g, 64.2 mmol) was added. The mixture was then heated at 80 ⁇ C. for 24 h, becoming homogenous after 3 h. Upon cooling to 25 ⁇ C., the product precipitated out of solution and was filtered rinsing with 1:1 hexanes/methylene chloride. After drying in vacuo, 6.9 g of compound 22A was isolated as a white powder. NMR spectroscopy showed only the endo isomer was isolated.
  • the resulting white solid was recrystallized twice with a 50/50 mixture of CH 2 Cl 2 /hexane and followed by a recrystallization with 100% ethyl acetate to yield 3.2 g of a final white solid which was a 1:10 mixture of compounds 34A & 6A.
  • anhydride-like intermediates which can be used in replacement of compounds 1A, 2A, or 7B are, but are not limited to, compounds 3A, 4A, 5A, 8B, 9A, 10A, 11A, 12A, 15A, 17A, 22A, 31A, 34A, 43A, and 50A.
  • LCMS YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • LCMS* YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 2 minutes containing 0.1 % TFA; 4 mL/min, monitoring at 220 nm.
  • LC YMC S5 ODS column 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm.
  • LC 51 54 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[3- Chloro-4-(4- morpholinyl)phenyl]- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 55 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (2,3-Dihydro-1H- inden-5-yl)-3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 60 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(1H- indol-5-yl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 61 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(1H- indazol-6-yl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 62 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (1,3-Benzodioxol-5- yl)-3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 63 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4- Amino-3- (trifluoromethyl)phenyl]- 3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 66 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (2,3-Dihydro-1,4- benzodioxin-6-yl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 67 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(4- methyl-2-oxo-2H-1- benzopyran-7-yl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 68 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(5- isoquinolinyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LCMS 51 69 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (2,5-Dimethoxy-4- nitrophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 70 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 2,3,5,6-Tetrafluoro-4- (1,3,3a,4,7,7a- hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2- yl)benzonitrile.
  • 51 71 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(2,4,5- trifluorophenyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 74 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (2,3-Dihydro-1H- indol-6-yl)-3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • 51 75 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3- Chloro-4- fluorophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LCMS 51 76 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (3,4-Dichlorophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 77 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(3,4,5- trichlorophenyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 80 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(2- methyl-1- naphthalenyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 81 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Chloro-3- methylphenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 82 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (3,4- Dimethylphenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 83 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4- Bromo-3- (trifluoromethyl) phenyl]-3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LCMS 51 84 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Bromo-3- methylphenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • 3.21 LC 51 85 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Fluoro-3- nitrophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 86 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4- Fluoro-3- (trifluoromethyl) phenyl]-3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 87 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Chloro-3- nitrophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 90 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (3,5-Dichloro-4- hydroxyphenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 91 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(4- hydroxy-3- nitrophenyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 92 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Amino-3- nitrophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 93 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2,2′- (2,3,5,6-Tetramethyl- 1,4- phenylene)bis[3a,4,7, 7a-tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione].
  • LC 51 98 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(5- Chloro-2-hydroxy-4- nitrophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 99 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(2- methoxy-3- dibenzofuranyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 100 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(2,3,4- trifluorophenyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • 51 101 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- (2,3-Dihydro-2- methyl-1,3-dioxo-1H- isoindol-5-yl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 105 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(6- Benzothiazolyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 106 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4- (1,3,3a,4,7,7a- Hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2-yl)-2- methoxybenzenecar- boxylic acid, methyl ester.
  • LC 51 119 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Amino-2,3,5,6- tetrafluorophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LC 51 120 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N- [2-Chloro-6-fluoro-4- (1,3,3a,4,7,7a- hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2- yl)phenyl]acetamide.
  • LC 51 121 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4- (1,3,3a,4,7,7a- Hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2-yl)-2- (trifluoromethyl) benzonitrile.
  • LC 51 122 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2- Fluoro-5- (1,3,3a,4,7,7a- hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2- yl)benzonitrile.
  • 25D or 38A 142 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-[4- (1,2,3-thiadiazol-4- yl)phenyl]-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • 25D or 38A 143 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N- [2-(1,3,3a,4,7,7a- Hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2-yl)-4- (trifluoromethyl) phenyl]acetamide.
  • 3.34 LC 25D or 38A 144 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N- [5-(1,3,3a,4,7,7a- Hexahydro-1,3-dioxo- 4,7-methano-2H- isoindol-2-yl)-3- (trifluoromethyl) phenyl]acetamide.
  • 3.34 LCMS 25D or 38A 145 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[3- Amino-5- (trifluoromethyl) phenyl]-3a,4,7,7a- tetrahydro-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • LCMS 25D or 38A 161 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )- 3a,4,7,7a- Tetrahydro-2-(3- methylphenyl)-4,7- methano-1H- isoindole-1,3(2H)- dione.
  • 2.53 LC 25D or 38A 162 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Bromophenyl)- 3a,4,7,7a-tetrahydro- 4,7-methano-1H- isoindole-1,3(2H)- dione.
  • LCMS YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • LCMS* YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 2 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • LC YMC S5 ODS column 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm.
  • LCMS 51 184 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(1H- Benzotriazol-5-yl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 185 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[3-Chloro- 4-(4-morpholinyl)phenyl]- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 186 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2,3- Dihydro-1H-inden-5-yl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione. 2.98 LCMS 51 187 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo- 1-naphthalenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 188 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Chloro- 1-naphthalenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 189 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(5-Amino- 1-naphthalenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 192 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(1H-indol-5- yl)-4,7-ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 193 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(1H-indazol-6- yl)-4,7-ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 194 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(1,3- Benzodioxol-5-yl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 195 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4-Amino- 3-(trifluoromethyl)phenyl]- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 196 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro- 4-iodophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 197 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(8-quinolinyl)- 4,7-ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 198 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(1,4- Benzodioxin-6-yl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 199 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-[2-oxo-4- (trifluoromethyl)-2H-1- benzopyran-7-yl]-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 200 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(4-methyl-2- oxo-2H-1-benzopyran-7-yl)- 4,7-ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 201 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(5- isoquinolinyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 202 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2,5- Dimethoxy-4-nitrophenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 203 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2,4,5- trifluorophenyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 204 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2,4,5- trichlorophenyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 205 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2-Amino- 4,5-dichlorophenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 206 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,4- Difluorophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 207 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-1-Acetyl-6- (1,3,3a,4,7,7a-hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-2,3-dihydro- 1H-indole.
  • LCMS 51 208 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-(3-Chloro-4- fluorophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 209 (3a ⁇ ,4 ⁇ ,7 ⁇ , 7a ⁇ )-2-(3,4- Dichlorophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 212 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro- 4-methylphenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 213 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2-methyl-1- naphthalenyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 214 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Chloro- 3-methylphenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 215 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,4- Dimethylphenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 218 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Fluoro- 3-nitrophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 219 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4-Fluoro- 3-(trifluoromethyl)phenyl]- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 222 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Chloro- 2-methoxy-5-methylphenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 223 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,5- Dichloro-4-hydroxyphenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 224 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(4-hydroxy-3- nitrophenyl)-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 225 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Amino- 3-nitrophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 226 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Amino- 2,3,5,6-tetramethylphenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 227 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(4-methyl-3- nitrophenyl)-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 228 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(3,4,5- trimethoxyphenyl)-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 229 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,4- Dimethoxyphenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 230 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(3-hydroxy-4- methoxyphenyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 231 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-6- (1,3,3a,4,7,7a-Hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-1,4(2H,3H)- phthalazinedione.
  • LCMS 51 232 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(4-methyl-5- nitro-2-pyridinyl)-4,7- ethano-1H-isoindole 1,3(2H)-dione.
  • LCMS 51 233 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-Chloro-4- (1,3,3a,4,7,7a-hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)- ⁇ - phenylbenzeneacetonitrile.
  • LCMS 51 234 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2-methoxy-3- dibenzofuranyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • 3.34 LCMS 51 235 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2,3,4- trifluorophenyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 241 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4- (1,3,3a,4,7,7a-Hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-2- methoxybenzoic acid, methyl ester.
  • LCMS 51 242 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-5- (1,3,3a,4,7,7a-Hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-2- methylbenzonitrile.
  • LCMS 51 243 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2-oxo-2H-1- benzopyran-6-yl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • LCMS 51 244 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2-methyl-8- quinolinyl)-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 245 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2,3,5,6- tetramethyl-4-nitrophenyl)- 4,7-ethano-1H-isoindole- 1,3(2H)-dione.
  • 3.16 LCMS 51 246 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2,4,5- trimethylphenyl)-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 249 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N-Ethyl-5- (1,3,3a,4,7,7a-hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-2-methyl-N- phenylbenzenesulfonamide.
  • 3.35 LCMS 51 250 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2,6- Dibromo-4-(1,3,3a,4,7,7a- hexahydro-1,3-dioxo-4,7- ethano-2H-isoindol-2- yl)benzenesulfonamide.
  • LCMS 51 251 (3a ⁇ ,4 ⁇ ,8 ⁇ ,8a ⁇ )-2-(2,3- Dimethyl-1H-indol-5-yl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 252 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3- Dibenzofuranyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 255 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(1,3- Dihydro-2,2- dioxidobenzo[c]thiophen-5- yl)hexahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 256 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2-hydroxy- 4,5-dimethylphenyl)-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 257 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(2,2,3,3- tetrafluoro-2,3-dihydro-1,4- benzodioxin-6-yl)-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • 3.63 LCMS 51 258 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(1H-indazol-5- yl)-4,7-ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 259 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Amino- 2,3,5,6-tetrafluorophenyl)- 3a,4,7,7a-tetrahydro-4,7- ethano-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 260 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo- 3-chlorophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 261 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-3a,4,7,7a- Tetrahydro-2-(5-hydroxy-1- naphthalenyl)-4,7-ethano- 1H-isoindole-1,3(2H)-dione.
  • 1.87 LCMS 51 262 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N-[2- Chloro-6-fluoro-4- (1,3,3a,4,7,7a-hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)phenyl]acetamide.
  • LCMS 51 263 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4- (1,3,3a,4,7,7a-Hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-2- (trifluoromethyl)benzonitrile 3.03 LCMS 51 264 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-5- (1,3,3a,4,7,7a-Hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)-2-(4- morpholinyl)benzoic acid, methyl ester.
  • LCMS 51 265 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-Fluoro-5- (1,3,3a,4,7,7a-hexahydro- 1,3-dioxo-4,7-ethano-2H- isoindol-2-yl)benzonitrile.
  • LCMS 51 266 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4- Bromophenyl)-3a,4,7,7a- tetrahydro-4,7-ethano-1H- isoindole-1,3(2H)-dione.
  • LCMS YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0. 1% TFA; 4 mL/min, monitoring at 220 nm.
  • LCMS* YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 2 minutes containing 0. 1% TFA; 4 mL/min, monitoring at 220 nm.
  • LC YMC S5 ODS column 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm.
  • LCMS 51 273 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(1,2,3,4-tetra- hydro-1-naphthalenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 274 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2,3-Di- hydro-1H-in- den-5-yl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 275 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4-(Octa- hydro-1,3,5-tri- oxo-4,7-ethano-2H-iso- indol-2-yl)-1-naph- thalenecarbonitrile.
  • LCMS 51 276 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Chloro-1-naph- thalenyl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 277 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(4-nitro-1-naph- thalenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 278 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2-naph- thalenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 279 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(5-quinolinyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 280 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(6-quinolinyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 281 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(4-meth- yl-2-oxo-2H-1-benzo- pyran-7-yl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 282 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(5-iso- quinolinyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 283 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,5-Di- nitrophenyl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 284 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2,5-Di- bromophenyl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 285 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2,4,5-tri- fluorophenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 286 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[2-Fluoro-5-tri- fluoromethyl)phenyl]tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 287 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2-Fluoro-5-methyl- phenyl)tetrahydr-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 288 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2,4,5-tri- chlorophenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 289 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2-Chloro-4-nitro- phenyl)tetrahydro-4,7-eth- ano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 290 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[2-Chloro-5-tri- fluoromethyl)phenyl]tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 291 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Fluoro- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 292 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,4-Di- fluorophenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 293 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,5-Di- fluorophenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 294 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 295 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro-4-fluoro- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 296 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,4-Di- chlorophenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 297 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(3,4,5-tri- chlorophenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 298 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro-4-methyl- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 299 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(3-iodo- phenyl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 300 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(3-nitro- phenyl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 301 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Acetyl- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 302 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[3-(tri- fluoromethyl)phenyl]-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 303 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,4-Di- methylphenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 304 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,5-Di- methylphenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 305 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Ethyl- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 306 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 307 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Fluoro-3-nitro- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 308 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4-Fluoro-3-(tri- fluoromethyl)phenyl]tetra- hydro-4,7-ethano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 309 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Chloro-3-nitro- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 310 (3a ⁇ ,4 ⁇ ,7 ⁇ 7a ⁇ )-Tetra- hydro-2-(4-iodo- phenyl)-4,7-ethano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 311 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(4-nitro- phenyl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 312 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[4-(1-methyl- ethyl)phenyl]-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 314 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4-(Octa- hydro-1,3,5-tri- oxo-4,7-ethano-2H-iso- indol-2-yl)benzeneacetonitrile 1.68 LCMS 51 315 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Ethyl- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 316 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4-[2-(Acetyl- oxy)ethyl]phenyl]tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 317 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(4-propyl- phenyl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 318 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2,3,4-tri- fluorophenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 319 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo-2,6-di- fluorophenyl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 320 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[4-nitro-3-(tri- fluoromethyl)phenyl]-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 321 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(6-Benzo- thiazolyl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 322 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2-meth- yl-8-quinolinyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • 2.01 LCMS 51 323 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Fluoro-3-methyl- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 324 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(1,3-Di- hydro-3-oxo-5-iso- benzofuranyl)tetrahydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 325 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N-[2-Nitro-4-(octa- hydro-1,3,5-trioxo-4,7-eth- ano-2H-isoindol-2-yl)phenyl]acetamide.
  • LCMS 51 326 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(2-Eth- yl-5-nitrophenyl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 327 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2-methyl-5-benzo- furanyl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 328 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(1H-inda- zol-5-yl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 329 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo-3-chloro- phenyl)tetrahydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 330 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[3-(tri- fluoromethoxy)phenyl]-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • 4.36 LCMS 51 331 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-4-(Octa- hydro-1,3,5-trioxo-4,7-ethano-2H-iso- indol-2-yl)-2-(tri- fluoromethyl)benzonitrile.
  • LCMS 51 332 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[2-(methylsulfonyl)-4-nitro- phenyl]-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 333 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,5-Di- bromophenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 334 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(3-iodo-4-methyl- phenyl)-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 335 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro-4-iodo- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 336 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(2-meth- yl-6-quinolinyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 337 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[2-(methyl- thio)-5-(trifluoromethyl)phenyl]-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 338 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo-2,6-di- ethylphenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • 3.35 LCMS 51 339 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[4-(trifluoro- methyl)phenyl]-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 340 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Chloro-3-methyl- phenyl)tetrahydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • 2.70 LCMS 51 341 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[4-(methoxy- methyl)-2-oxo-2H-1-benzo- pyran-7-yl]-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 342 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N-Meth- yl-3-(octahydro-1,3,5-trioxo-4,7-eth- ano-2H-isoindol-2-yl)benzmide.
  • LCMS 51 343 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(6-Acetyl-1,3-benzo- dioxol-5-yl)tetra- hydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 344 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(3,4,5-trifluoro- phenyl)-4,7-ethano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 345 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-Bromo-5-(octa- hydro-1,3,5-trioxo-4,7-ethano-2H-iso- indol-2-yl)benzoic acid, methyl ester.
  • LCMS 51 346 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3-Chloro-4-nitro- phenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 347 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[5-[(Di- fluoromethyl)sulfonyl]-2-methoxy- phenyl]tetrahydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 51 348 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-(1-naphthalenyl)-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 51 349 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(4-Bromo-1-naph- thalenyl)tetrahydro-4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LCMS 13C 350 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-(3,5-Di- chlorophenyl)tetrahydro-4,7-ethano-1H-iso- indole-1,3,5(2H,4H)-trione.
  • LCMS 13C 351 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-2-[4-Bromo-3-(tri- fluoromethyl)phenyl]tetra- hydro-4,7-ethano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LC 13C 363 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-Tetra- hydro-2-[3-(1-methyl- ethyl)phenyl]4,7-eth- ano-1H-isoindole-1,3,5(2H,4H)-trione.
  • LC 13C 364 (3a ⁇ ,4 ⁇ ,7 ⁇ ,7a ⁇ )-N-(1,1-Di- methylethyl)-5-(octahydro-1,3,5-tri- oxo-4,7-ethano-2H-iso- indol-2-yl)-1-naphthalene- sulfonamide.
  • LCMS YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • LCMS* YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 2 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • Example 367 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-2-(3,4-Di- chlorophenyl)-4,4a,5,5a,6,6a-hexa- hydro-4,6-ethanocycloprop[f]iso- indole-1,3(2H,3aH)-dione.
  • LCMS 51 380 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-4,4a,5,5a,6,6a-Hexa- hydro-2-(5-quinolinyl)-4,6-ethano- cycloprop[f]isoindole-1,3(2H,3aH)-dione.
  • 2.25 LCMS 51 381 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-4,4a,5,5a,6,6a-Hexa- hydro-2-(6-quinolinyl)-4,6-ethano- cycloprop[f]isoindole-1,3(2H,3aH)-dione.
  • LCMS 51 404 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-2-(3-Ethyl- phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethano- cycloprop[f]isoindole-1,3(2H,3aH)-dione.
  • LCMS 51 405 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-4-(Octa- hydro-1,3-dioxo-4,6-ethanocyclo- prop[f]isoindol-2(1H)-yl)benzonitrile.
  • LCMS 51 419 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-2-[4-(1,1-Di- methylethyl)-3-nitrophenyl]-4,4a,5,5a,6,6a-hexa- hydro-4,6-ethanocycloprop[f]iso- indole-1,3(2H,3aH)-dione 3.76 LCMS 51 420 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-2-(4-Bromo-2,6-di- fluorophenyl)-4,4a,5,5a,6,6a-hexa- hydro-4,6-ethanocycloprop[f]iso- indole-1,3(2H,3aH)-dione.
  • LCMS 51 424 (3a ⁇ ,4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,6a ⁇ )-2-(1,3-Di- hydro-3-oxo-5-isobenzofuranyl)-4,4a,5,5a,6,6a-hexa- hydro-4,6-ethanocycloprop[f]isoindole-1,3(2H,3aH)-dione.
  • LCMS YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • LCMS* YMC S5 ODS column, 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 2 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
  • LC YMC S5 ODS column 4.6 ⁇ 50 mm eluting with 10-90% MeOH/H 2 O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm.
  • LCMS 51 463 2-(2,3-Dihydro-1H-inden- 5-yl)hexahydro-1H- isoindole-1,3(2H)-dione. 3.17 LCMS 51 464 2-(4-Bromo-1- naphthalenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 3.17 LCMS 51 465 2-(4-Chloro-1- naphthalenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 466 Hexahydro-2-(3-iodo-4- methylphenyl)-1H- isoindole-1,3(2H)-dione. 3.55 LCMS 51 467 Hexahydro-2-(4-nitro-1- naphthalenyl)-1H- isoindole-1,3(2H)-dione. 3.09 LCMS 51 468 Hexahydro-2-(1H-indol-5- yl)-1H-isoindole-1,3(2H)- dione.
  • LCMS 51 469 Hexahydro-2-(5- quinolinyl)-1H-isoindole- 1,3(2H)-dione.
  • 2.03 LCMS 51 470 Hexahydro-2-(1H-indazol- 6-yl)-1H-isoindole- 1,3(2H)-dione.
  • 2.56 LCMS 51 471 2-(1,3-Benzodioxol-5- yl)hexahydro-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 472 2-(3-Fluoro-4- methylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 3.06 LCMS 51 473 Hexahydro-2-[4-nitro-3- (trifluoromethyl)phenyl]- 1H-isoindole-1,3(2H)- dione. 0.29 LCMS 51 474 Hexahydro-2-(8- quinolinyl)-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 475 2-(2,3-Dihydro-1,4- benzodioxin-6- yl)hexahydro-1H- isoindole-1,3(2H)-dione. 2.76 LCMS 51 476 Hexahydro-2-(4-methyl-2- oxo-2H-1-benzopyran-7- yl)-1H-isoindole-1,3(2H)- dione. 0.31 LCMS 51 477 Hexahydro-2-(5- isoquinolinyl)-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 478 Hexahydro-2-(2,4,5- trifluorophenyl)-1H- isoindole-1,3(2H)-dione. 0.27 LCMS 51 479 Hexahydro-2-(2,4,5- trichlorophenyl)-1H- isoindole-1,3(2H)-dione. 3.11 LCMS 51 480 Hexahydro-2-(2,3,4,6- tetrafluorophenyl)-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 481 2-(3,4- Difluorophenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 482 1-Acetyl-2,3-dihydro-6- (octahydro-1,3-dioxo-2H- isoindol-2-yl)-1H-indole.
  • LCMS 51 483 2-(3-Chloro-4- fluorophenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 487 2-(3-Chloro-4- methylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 3.25 LCMS 51 488 Hexahydro-2-(2-methyl-1- naphthalenyl)-1H- isoindole-1,3(2H)-dione. 3.04 LCMS 51 489 2-(4-Chloro-3- methylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 3.23 LCMS 51 490 2-(3,4- Dimethylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 491 2-[4-Bromo-3- (trifluoromethyl)phenyl]hexahydro-1H-isoindole- 1,3(2H)-dione. 1.23 LCMS 51 492 2-(4-Bromo-3- methylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 3.30 LCMS 51 493 2-(4-Fluoro-3- nitrophenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 494 2-[4-Fluoro-3- (trifluoromethyl)phenyl]hexahydro-1H-isoindole- 1,3(2H)-dione. 1.23 LCMS 51 495 2-(4-Chloro-3- nitrophenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 3.10 LCMS 51 496 2-[4-Chloro-3- (trifluoromethyl)phenyl]hexahydro-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 497 2-(4-Chloro-2-methoxy-5- methylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 2.90 LCMS 51 498 2-(3-Fluoro-4- methoxyphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 2.80 LCMS 51 499 2-Bromo-5-(octahydro-1,3- dioxo-2H-isoindol-2- yl)benzoic acid, methyl ester.
  • LCMS 51 500 Hexahydro-2-(4-methyl-3- nitrophenyl)-1H-isoindole- 1,3(2H)-dione. 3.01 LCMS 51 501 Hexahydro-2-(3,4,5- trimethoxyphenyl)-1H- isoindole-1,3(2H)-dione. 2.65 LCMS 51 502 2-(3,4- Dimethoxyphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 503 Hexahydro-2-[2-(2- pyridinyl)-1H- benzimidazol-5-yl]-1H- isoindole-1,3(2H)-dione. 2.41 LCMS 51 504 2-(9-Ethyl-9H-carbazol-3- yl)hexahydro-1H- isoindole-1,3(2H)-dione. 3.39 LCMS 51 505 Hexahydro-2-(2-methoxy- 3-dibenzofuranyl)-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 506 Hexahydro-2-(2,3,4- trifluorophenyl)-1H- isoindole-1,3(21H1)-dione.
  • LCMS 51 507 Hexahydro-2-methyl-5- (octahydro-1,3-dioxo-2H- isoindol-2-yl)-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 508 Hexahydro-2-[6- (methylthio)-5-nitro-8- quinolinyl]-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 509 2-[2,5-Dichloro-4-(1H- pyrrol-1- yl)phenyl]hexahydro-1H- isoindole-1,3(2H)-dione.
  • LCMS 51 510 Hexahydro-2-(6-methyl-5- quinolinyl)-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 511 N-(1,1-Dimethylethyl)-5- (octahydro-1,3-dioxo-2H- isoindol-2-yl)-1- naphthalenesulfonamide.
  • LCMS 51 512 Hexahydro-2-[4- (methoxymethyl)-2-oxo- 2H-1-benzopyran-7-yl]- 1H-isoindole-1,3(2H)- dione. 2.82 LCMS 51 513 2-(6- Benzothiazolyl)hexahydro- 1H-isoindole-1,3(2H)- dione. 2.65 LCMS 51 514 2-Methoxy-4-(octahydro- 1,3-dioxo-2H-isoindol-2- yl)benzoic acid, methyl ester.
  • LCMS 51 515 2-Methyl-5-(octahydro- 1,3-dioxo-2H-isoindol-2- yl)benzonitrile. 2.85 LCMS 51 516 Hexahydro-2-(2-oxo-2H-1- benzopyran-6-yl)-1H- isoindole-1,3(2H)-dione. 2.64 LCMS 51 517 Hexahydro-2-(2-methyl-8- quinolinyl)-1H-isoindole- 1,3(2H)-dione.
  • LCMS 51 518 2-[3,5- Bis(trifluoromethyl)phenyl]hexahydro-1H-isoindole- 1,3(2H)-dione.
  • 3.51 LCMS 51 519 Hexahydro-2-(2,4,5- trimethylphenyl)-1H- isoindole-1,3(2H)-dione.
  • 3.16 LCMS 51 520 2-(4-Fluoro-3- methylphenyl)hexahydro- 1H-isoindole-1,3(2H)- dione.
  • LCMS 51 521 Hexahydro-2-(3-methoxy- 4-methylphenyl)-1H- isoindole-1,3(2H)-dione. 0.98 LCMS 51 522 N-Ethyl-2-methyl-5- (octahydro-1,3-dioxo-2H- isoindol-2-yl)-N- phenylbenzenesulfonamide. 3.01 LCMS 51 523 2-(2,3-Dimethyl-1H-indol- 5-yl)hexahydro-1H- isoindole-1,3(2H)-dione.
US10/075,870 2001-02-27 2002-02-14 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function Abandoned US20040087548A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/075,870 US20040087548A1 (en) 2001-02-27 2002-02-14 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US11/311,731 US7655688B2 (en) 2001-02-27 2005-12-19 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27167201P 2001-02-27 2001-02-27
US10/075,870 US20040087548A1 (en) 2001-02-27 2002-02-14 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/311,731 Continuation US7655688B2 (en) 2001-02-27 2005-12-19 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Publications (1)

Publication Number Publication Date
US20040087548A1 true US20040087548A1 (en) 2004-05-06

Family

ID=23036570

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/075,870 Abandoned US20040087548A1 (en) 2001-02-27 2002-02-14 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US11/311,731 Active 2025-01-28 US7655688B2 (en) 2001-02-27 2005-12-19 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/311,731 Active 2025-01-28 US7655688B2 (en) 2001-02-27 2005-12-19 Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Country Status (6)

Country Link
US (2) US20040087548A1 (US07655688-20100202-C00053.png)
EP (1) EP1379249A4 (US07655688-20100202-C00053.png)
JP (1) JP2004523558A (US07655688-20100202-C00053.png)
CA (1) CA2439265A1 (US07655688-20100202-C00053.png)
HU (1) HUP0304055A2 (US07655688-20100202-C00053.png)
WO (1) WO2002067939A1 (US07655688-20100202-C00053.png)

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040077606A1 (en) * 2000-06-28 2004-04-22 Salvati Mark E. Fused cyclic modulators of nuclear hormone receptor function
US20050187273A1 (en) * 2001-12-19 2005-08-25 Salvati Mark E. Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function
US20050192253A1 (en) * 2000-09-19 2005-09-01 Salvati Mark E. Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20060079686A1 (en) * 2004-08-06 2006-04-13 Ellen Baxter Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)
US20060079687A1 (en) * 2004-08-06 2006-04-13 Ellen Baxter Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)
US20060178383A1 (en) * 2004-08-06 2006-08-10 Bischoff Francois P Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)
US20060264459A1 (en) * 2000-06-28 2006-11-23 Salvati Mark E Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20070112044A1 (en) * 2003-10-10 2007-05-17 Kyowa Hakko Kogyo Co., Ltd. Thiadiazoline derivative
US20070155804A1 (en) * 2003-04-18 2007-07-05 Kyowa Hakko Kogyo Co., Ltd. Of Tokyo, Japan Fuji Photo Film Co., Ltd. Kanagawa, Japan Mitotic kinesin inhibitor
US20070232630A1 (en) * 2006-02-06 2007-10-04 Baxter Ellen W MACROCYCLE DERIVATIVES USEFUL AS INHIBITORS OF beta-SECRETASE (BACE)
US20070232642A1 (en) * 2006-02-06 2007-10-04 Baxter Ellen W 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US20070276017A1 (en) * 2003-06-10 2007-11-29 Chikara Murakata Thiadiazoline Derivative
US20080194653A1 (en) * 2005-03-22 2008-08-14 Kyowa Hakko Kogyo Co., Ltd. Therapeutic Agent For Solid Tumor
US20080194624A1 (en) * 2006-02-06 2008-08-14 Ellen Baxter 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US20080207706A1 (en) * 2001-12-11 2008-08-28 Kyowa Hakko Kogyo Co., Ltd Thiadiazoline derivative
US20080262049A1 (en) * 2005-03-22 2008-10-23 Kyowa Hakko Kogyo Co., Ltd. Therapeutic Agent for Hematopoietic Tumor
US20090227581A1 (en) * 2008-01-29 2009-09-10 Ellen Baxter 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US20090227627A1 (en) * 2008-01-28 2009-09-10 Ellen Baxter 6-substituted-thio-2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US20100029625A1 (en) * 2005-06-24 2010-02-04 Kyowa Hakko Kirin Co., Ltd. Therapeutic Agent for Restenosis
US8633178B2 (en) 2011-11-23 2014-01-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8933059B2 (en) 2012-06-18 2015-01-13 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
CN106349160A (zh) * 2016-08-05 2017-01-25 浙江工业大学 一种8‑氨基喹啉衍生物及其制备与应用
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
CN107954992A (zh) * 2017-12-15 2018-04-24 田元强 吡咯二酮衍生物及其在小菜蛾和桃蚜防治中的应用
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
CN113620969A (zh) * 2020-05-07 2021-11-09 贵州医科大学 带桥环的环己烷二羧酸衍生物及其药物组合物和应用
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002950217A0 (en) 2002-07-16 2002-09-12 Prana Biotechnology Limited 8- Hydroxy Quinoline Derivatives
US7737168B2 (en) 2003-06-20 2010-06-15 Siga Technologies, Inc. Compounds, compositions, and methods for treatment and prevention of orthopoxvirus infections and associated diseases
DK1638938T3 (en) * 2003-06-20 2017-07-31 Siga Tech Inc Compounds, Compositions and Methods for the Treatment and Prevention of Orthopox Virus Infections and Related Diseases
US8530509B2 (en) 2003-06-20 2013-09-10 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
EP1836202B1 (en) * 2005-01-10 2016-12-21 Acadia Pharmaceuticals Inc. Aminophenyl derivatives as selective androgen receptor modulators
US7468439B2 (en) * 2006-09-06 2008-12-23 Bristol-Myers Squibb Company Alkylene bridged sultam compounds useful as modulators of nuclear hormone receptor function
CN101702904A (zh) 2007-04-23 2010-05-05 西佳技术公司 用于治疗和预防正痘病毒感染和相关疾病的化合物、组合物和方法
US8466171B2 (en) * 2007-11-01 2013-06-18 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as modulators of nuclear hormone receptor function
DE102008022221A1 (de) * 2008-05-06 2009-11-12 Universität des Saarlandes Inhibitoren der humanen Aldosteronsynthase CYP11B2
AU2009260503B2 (en) 2008-05-27 2014-03-27 The Board Of Regents Of The University Of Texas System Wnt protein signalling inhibitors
EP2455370A1 (en) 2009-07-17 2012-05-23 Shionogi&Co., Ltd. Pharmaceutical product containing lactam or benzene sulfonamide compound
EP2549871B1 (en) 2010-03-23 2018-08-22 Siga Technologies, Inc. Polymorphic form st-246 and methods of preparation
JP5697800B2 (ja) * 2011-07-21 2015-04-08 シュエンジュウ・ファーマ・カンパニー・リミテッド 複素環置換ピリミジン化合物
CN103193696B (zh) * 2013-04-18 2015-11-11 北京大学 降冰片烯基酰亚胺体系甲壳型聚合物单体及其聚合物
GB201507937D0 (en) * 2015-05-08 2015-06-24 Univ Hertfordshire Higher Education Corp Compounds for treatment of pancreatic cancer
CN110914240B (zh) * 2015-11-30 2024-02-20 奥塔哥创新有限公司 释放一氧化碳的降冰片烯酮化合物
US10596168B2 (en) 2016-04-27 2020-03-24 Forschungsverbund Berlin E.V. Antagonists of the thyroid-stimulating hormone receptor (TSHR)
CN110183456A (zh) * 2019-07-11 2019-08-30 河南师范大学 一种2-芳基吲唑琥珀酰亚胺螺环化合物的合成方法
WO2023192782A2 (en) * 2022-03-27 2023-10-05 Board Of Regents, The University Of Texas System Small molecule inhibitors of lanosterol synthase

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5532372A (en) * 1990-07-06 1996-07-02 Sumitomo Pharmaceuticals Company, Ltd. Imide derivatives, and their production and use
US6017924A (en) * 1996-06-27 2000-01-25 Ligand Pharmaceuticals Incorporated Androgen receptor modulator compounds and methods
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US20020173445A1 (en) * 2000-06-28 2002-11-21 Salvati Mark E. Selective androgen receptor modulators and methods for their identification, design and use
US20030181728A1 (en) * 2001-12-19 2003-09-25 Salvati Mark E. Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function
US20040019063A1 (en) * 2002-05-17 2004-01-29 Chongqing Sun Bicyclic modulators of androgen receptor function
US20040077606A1 (en) * 2000-06-28 2004-04-22 Salvati Mark E. Fused cyclic modulators of nuclear hormone receptor function
US20040181064A1 (en) * 2002-05-17 2004-09-16 Chong-Qing Sun Bicyclic modulators of androgen receptor function

Family Cites Families (117)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3320270A (en) 1963-10-08 1967-05-16 Tri Kem Corp Certain 2-acylimidothiazole compounds
US3215597A (en) 1963-10-30 1965-11-02 Dow Chemical Co Methods and compositions for use in animal husbandry
US3343940A (en) 1964-06-12 1967-09-26 Pennsalt Chemicals Corp Process for plant desiccation
US3261845A (en) 1964-07-14 1966-07-19 Dow Chemical Co N-phenyl derivatives of 3,6-epoxyhexahydrophthalimide
GB1039020A (en) 1964-09-21 1966-08-17 Biorex Laboratories Ltd Process for the preparation of 5-nitrofurfuraldehyde diacetate
US3428538A (en) 1966-01-13 1969-02-18 Peter Scheiner Method for preparing aziridines by photolysis of triazolines
JPS4916937B1 (US07655688-20100202-C00053.png) 1970-01-21 1974-04-25
US3965264A (en) 1971-12-20 1976-06-22 Petrolite Corporation Process for controlling microbiological organisms in aqueous or petroleum hydrocarbon systems
US3923490A (en) 1971-12-20 1975-12-02 Petrolite Corp Use of 1,2-dihydro-pyridine-N-phosphonates and thiophosphonates as microbiocides
US3998833A (en) 1971-12-20 1976-12-21 Petrolite Corporation Diels-alder adducts of dihydro-nitrogen heterocyclic phosphoramidates
US4089650A (en) 1971-12-20 1978-05-16 Petrolite Corporation Use of Diels-Alder adducts of dihydro-nitrogen heterocyclic phosphoramidates as corrosion inhibitors
US3821232A (en) 1971-12-20 1974-06-28 Petrolite Corp 1,2-dihydro-pyridine-n-phosphonates and thiophosphonates
JPS5032306B2 (US07655688-20100202-C00053.png) 1972-11-02 1975-10-20
US3925554A (en) 1972-11-30 1975-12-09 Sumitomo Chemical Co Certain 3,5-dichlorophenyl compound used as a plant fungicide
NL7501563A (nl) 1974-02-28 1975-09-01 Merck & Co Inc Werkwijze voor het bereiden van preparaten te- gen het samenpakken van bloedplaatjes.
US3997293A (en) 1974-03-19 1976-12-14 Petrolite Corporation Use of dihydro-nitrogen heterocyclic phosphoramidates as corrosion inhibitors
FR2329276A1 (fr) 1975-10-29 1977-05-27 Roussel Uclaf Nouvelles imidazolidines substituees, procede de preparation, application comme medicament et compositions les renfermant
DE2862100D1 (en) 1977-10-12 1983-01-05 Ici Plc Acylanilides, process for their manufacture and pharmaceutical and veterinary compositions containing them
CA1138334A (en) 1977-10-28 1982-12-28 Karl Bernauer Pharmaceutical preparations containing certain urea derivatives
MC1220A1 (fr) 1977-10-28 1979-07-20 Hoffmann La Roche Nouveaux derives d'imidazolidine
US4191775A (en) 1977-12-15 1980-03-04 Imperial Chemical Industries Limited Amide derivatives
FR2465486A1 (fr) 1979-09-21 1981-03-27 Roussel Uclaf Nouvelle application utilisant la lh-rh ou des agonistes
FR2492381A1 (fr) 1980-10-21 1982-04-23 Science Union & Cie Nouveaux acides aza bicyclo alcane carboxyliques substitues leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme
DE3121152A1 (de) 1981-05-22 1982-12-09 Schering Ag, 1000 Berlin Und 4619 Bergkamen "verwendung der kombination eines aromatase-hemmers mit einem antiandrogen zur prophylaxe und therapie der prostatahyperplasie"
US4753957A (en) 1981-09-28 1988-06-28 Rohm And Haas Company Substituted 2,4-imidazolidinediones and fungicidal compositions
US4584364A (en) 1984-02-06 1986-04-22 The Boeing Company Phenolic-capped imide sulfone resins
US5512676A (en) 1987-09-03 1996-04-30 The Boeing Company Extended amideimide hub for multidimensional oligomers
US4851495A (en) 1987-02-20 1989-07-25 The Boeing Company Polyetherimide oligomer
US4536559A (en) 1983-06-17 1985-08-20 The Boeing Company Thermally stable polyimide polysulfone compositions for composite structures
US5693741A (en) 1988-03-15 1997-12-02 The Boeing Company Liquid molding compounds
US5780583A (en) 1991-01-09 1998-07-14 The Boeing Company Reactive polyarylene sulfide oligomers
US5367083A (en) 1987-09-03 1994-11-22 The Boeing Company Extended acid halide capping monomers
US5516876A (en) 1983-09-27 1996-05-14 The Boeing Company Polyimide oligomers and blends
US5446120A (en) 1985-10-07 1995-08-29 The Boeing Company Polyethersulfone oligomers and blends
US5155206A (en) 1987-09-03 1992-10-13 The Boeing Company Crosslinkable polyamideimide oligomers and a method of preparation
US5645925A (en) 1988-03-14 1997-07-08 Boeing Company Advanced composite blends
US5286811A (en) 1983-09-27 1994-02-15 The Boeing Company Blended polyimide oligomers and method of curing polyimides
US5210213A (en) 1983-06-17 1993-05-11 The Boeing Company Dimensional, crosslinkable oligomers
US5116935A (en) 1987-05-04 1992-05-26 The Boeing Company Polyimide oligomers and blends and method of curing
US5104967A (en) 1987-09-03 1992-04-14 The Boeing Company Amideimide oligomers and blends
US4507303A (en) 1981-12-22 1985-03-26 Sumitomo Chemical Company, Limited Succinimide derivatives, compositions and method of use
DE3382406D1 (de) 1982-04-08 1991-10-17 Shell Int Research Neue hydantoine, ihre herstellung und verwendung.
DE3227055A1 (de) 1982-07-20 1984-01-26 Hoechst Ag, 6230 Frankfurt Neue derivate der 2-aza-bicyclo(2.2.2)octan-3-carbonsaeure, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung sowie 2-aza-bicyclo(2.2.2)octan-3-carbonsaeure als zwischenstufe und verfahren zu deren herstellung
US4473393A (en) 1982-08-06 1984-09-25 Buffalo Color Corporation Pesticidal thiohydantoin compositions
JPS59118750A (ja) 1982-12-27 1984-07-09 Eisai Co Ltd カルボン酸アミド化合物およびその誘導体
US4980481A (en) 1983-06-17 1990-12-25 The Boeing Company End-cap monomers and oligomers
US5112939A (en) 1983-06-17 1992-05-12 The Boeing Company Oligomers having pyrimidinyl end caps
US4476184A (en) 1983-08-09 1984-10-09 The Boeing Company Thermally stable polysulfone compositions for composite structures
US4582886A (en) 1984-02-27 1986-04-15 General Electric Company Heat curable epoxy resin compositions and epoxy resin curing agents
US4562255A (en) 1984-03-30 1985-12-31 American Home Products Corporation Substituted bi-alicyclic imides
US4533737A (en) 1984-04-02 1985-08-06 General Electric Company Silicon functionalized norbornane carboxyimide and methods for making
GB8411928D0 (en) 1984-05-10 1984-06-13 Robinson Bros Ltd Preparing substituted oxazolines
US4666885A (en) 1985-02-08 1987-05-19 Fernand Labrie Combination therapy for treatment of female breast cancer
US4659695A (en) 1985-02-08 1987-04-21 Fernand Labrie Method of treatment of prostate cancer
US4775660A (en) 1984-08-02 1988-10-04 Fernand Labrie Treatment of breast cancer by combination therapy
US4760053A (en) 1984-08-02 1988-07-26 Fernand Labrie Combination therapy for selected sex steroid dependent cancers
US4670536A (en) 1985-06-01 1987-06-02 Director-General Of Agency Of Industrial Science And Technology Addition-curable quinoxaline resin oligomer and intermediate material for fiber-reinforced composite
US5594089A (en) 1985-09-05 1997-01-14 The Boeing Company Heterocycle or heterocycle sulfone oligomers with multiple chemically functional end caps
US4656235A (en) 1985-09-05 1987-04-07 Polytechnic Institute Of New York Siloxane-containing polyimide coatings for electronic devices
US5610317A (en) 1985-09-05 1997-03-11 The Boeing Company Multiple chemically functional end cap monomers
US5151487A (en) 1985-09-30 1992-09-29 The Boeing Company Method of preparing a crosslinking oligomer
US4892943A (en) 1985-10-16 1990-01-09 American Home Products Corporation Fused bicyclic imides with psychotropic activity
GB8617653D0 (en) 1986-07-18 1986-08-28 Ici Plc Amide derivatives
US5084472A (en) 1986-11-04 1992-01-28 Roussel Application of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4'-dimethylimidazoline 2,5-dione in the treatment of hormone-dependent cancers other than that of the prostate
FR2619381B1 (fr) 1987-08-13 1989-12-08 Roussel Uclaf Nouvelles imidazolidines substituees par un radical hydroxymethyle et un radical phenyl substitue, leur procede de preparation, leur application comme medicaments, les compositions pharmaceutiques les renfermant et un intermediaire pour leur preparation
US4892578A (en) 1987-11-06 1990-01-09 Fmc Corporation Phenylmethyl-4,4-dimethyl-3-isoxazolidinone plant regulators
US5817744A (en) 1988-03-14 1998-10-06 The Boeing Company Phenylethynyl capped imides
US5595985A (en) 1989-03-10 1997-01-21 Endorecherche Inc. Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
DK0462189T3 (da) 1989-03-10 1995-11-20 Endorecherche Inc Kombinationsterapi til behandling af østrogenfølsomme sygdomme
FR2649110B1 (fr) 1989-06-29 1994-10-21 Adir Nouveaux derives peptidiques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
DE69034148T2 (de) 1989-07-07 2005-06-30 Endorecherche Inc., Ste-Foy Kombinationstherapie zur Prophylaxe und/oder Behandlung von gutartiger prostatischer Hyperplasie
FR2656302B1 (fr) 1989-12-22 1992-05-07 Roussel Uclaf Nouveau procede de preparation de l'anandron et derives de l'anandron.
US5114612A (en) 1990-04-04 1992-05-19 The United States Of America As Represented By The Department Of Energy Liquid crystal polyester thermosets
US5093500A (en) 1990-10-17 1992-03-03 Shell Oil Company Spirodilactam bisimides
HUT62296A (en) 1990-12-18 1993-04-28 Sandoz Ag Herbicidal composition comprising hydantoin derivative as active ingredient and process for producing the active ingredient
FR2671348B1 (fr) 1991-01-09 1993-03-26 Roussel Uclaf Nouvelles phenylimidazolidines, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant.
US5411981A (en) 1991-01-09 1995-05-02 Roussel Uclaf Phenylimidazolidines having antiandrogenic activity
USRE35956E (en) 1991-01-09 1998-11-10 Roussel Uclaf Phenylimidazolidines having antiandrogenic activity
FR2694290B1 (fr) 1992-07-08 1994-09-02 Roussel Uclaf Nouvelles phénylimidazolidines éventuellement substituées, leur procédé de préparation, leur application comme médicaments et les compositions pharmaceutiques les renfermant.
IL107719A0 (en) 1992-12-21 1994-02-27 Du Pont Imidazolones their manufacture and their use as herbicides
EP0611885B1 (de) 1993-02-17 1997-06-04 New Sulzer Diesel AG Brennstoffeinspritzventil für eine Hubkolbenbrennkraftmaschine
US5399725A (en) 1993-05-27 1995-03-21 Bristol-Myers Squibb Co. 7-oxabicycloheptane carboxylic acid prostaglandin analog intermediates useful in the preparation of anti-thrombotic and anti-vasospastic compounds and method for preparing same
TW521073B (en) 1994-01-05 2003-02-21 Hoechst Marion Roussel Inc New optionally substituted phenylimidazolidines, their preparation process, their use as anti-androgenic agent and the pharmaceutical compositions containing them
FR2716110B1 (fr) 1994-02-16 1996-04-05 Roussel Uclaf Compositions cosmétiques ou pharmaceutiques comprenant des liposomes.
US5539126A (en) 1994-04-20 1996-07-23 Bristol-Myers Squibb Company Method for preparing homochiral maleimide intermediates, via silylation techniques
GB9411800D0 (en) 1994-06-13 1994-08-03 Sandoz Ltd Organic compounds
DE69519582D1 (de) 1994-09-14 2001-01-11 Univ Sheffield Kontrolle des haarwuchses
FR2742749B1 (fr) 1995-12-22 1998-02-06 Roussel Uclaf Nouvelles phenylimidazolidines comportant notamment un radical nitrooxy ou carbonyloxy, procede et intermediaires de preparation, application comme medicaments, nouvelles utilisations et compositions pharmaceutiques
US6673927B2 (en) 1996-02-16 2004-01-06 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Farnesyl transferase inhibitors
WO1998018783A1 (fr) 1996-10-25 1998-05-07 Daiichi Pharmaceutical Co., Ltd. Derives d'amine tricycliques
US6071957A (en) 1996-11-27 2000-06-06 The University Of Tennessee Research Corporation Irreversible non-steroidal antagonist compound and its use in the treatment of prostate cancer
US5929146A (en) 1996-12-27 1999-07-27 Minnesota Mining And Manufacturing Company Modifying agents for polyolefins
FR2764890B1 (fr) 1997-06-24 1999-08-27 Adir Nouveaux derives chromeniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
PL337888A1 (en) 1997-07-03 2000-09-11 Du Pont Pharm Co Imidazoprimidines and imidazopyridines for use in treating neurological disorders
NZ503001A (en) 1997-08-28 2002-09-27 Vela Pharmaceuticals Inc Use of an androgen antagonist in therapies for anorexia, anorexia nervosa, and disorders characterized by a pathologically underweight condition
ES2154252T3 (es) * 1997-12-22 2005-12-01 Bayer Pharmaceuticals Corp. Inhibicion de quinasa p38 utilizando difenil-ureas simetricas y asimetricas.
WO2000013508A1 (en) 1998-09-09 2000-03-16 Ishihara Sangyo Kaisha, Ltd. Fused-benzene derivatives useful as herbicides
US6297380B1 (en) 1998-11-23 2001-10-02 Pfizer Inc. Process and intermediates for growth hormone secretagogues
DE69909947T2 (de) 1998-12-02 2004-02-12 Nippon Paper Industries Co. Ltd. Tintenstrahlaufzeichnungsblatt mit einer Bildschutzschicht
JP2000169474A (ja) 1998-12-07 2000-06-20 Kotobuki Seiyaku Kk イソキヌクリジン誘導体及びその製造方法並びにこれを含有する高コレステロール血症治療剤
AU1928800A (en) 1998-12-22 2000-07-12 Eli Lilly And Company Substituted tricyclics
DK1140941T3 (da) 1998-12-23 2005-02-14 Bristol Myers Squibb Pharma Co Nitrogenholdige heterobicykliske forbindelser som faktor Xa-inhibitorer
GB9918962D0 (en) 1999-08-11 1999-10-13 Cerebrus Ltd Chemical compounds xxii
GB9921150D0 (en) 1999-09-07 1999-11-10 Merck Sharp & Dohme Therapeutic agents
DK1218382T3 (da) 1999-10-08 2004-03-22 Gruenenthal Gmbh Bicykliske imidazo-3-ylaminderivater
US6200573B1 (en) 1999-12-03 2001-03-13 Starcor Pharmaceuticals, Inc. Method of medical management for lower urinary tract symptoms and benign prostatic hyperplasia
US6403588B1 (en) 2000-04-27 2002-06-11 Yamanouchi Pharmaceutical Co., Ltd. Imidazopyridine derivatives
US20040077605A1 (en) 2001-06-20 2004-04-22 Salvati Mark E. Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
EP1319007B9 (en) * 2000-09-19 2007-10-10 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US6953679B2 (en) 2000-09-19 2005-10-11 Bristol-Myers Squibb Company Method for the preparation of fused heterocyclic succinimide compounds and analogs thereof
ATE415396T1 (de) 2000-09-20 2008-12-15 Ortho Mcneil Pharm Inc Pyrazine derivate als tyrosin kinase modulatoren
US6545017B1 (en) 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
FR2818277B1 (fr) 2000-12-14 2003-01-24 Servier Lab Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
CZ20032185A3 (en) 2001-03-09 2004-06-16 Pfizer Products Inc. Triazolopyridines as anti-inflammatory agents
EP1379245A4 (en) 2001-04-18 2006-07-26 Bristol Myers Squibb Co 1, 4, 5, 6-TETRAHYDROPYRAZOLO- 3, 4-C-PYRIDINE-7-ONE AS FACTOR XA HEMMER
WO2003011824A1 (en) 2001-07-31 2003-02-13 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
PT1534707E (pt) 2002-06-19 2007-12-19 Janssen Pharmaceutica Nv Derivados de 2,4-di-hidro-pirrolo(3,4-b)-quinolin-9-ona substituídos, úteis como inibidores da fosfodiesterase

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5532372A (en) * 1990-07-06 1996-07-02 Sumitomo Pharmaceuticals Company, Ltd. Imide derivatives, and their production and use
US6017924A (en) * 1996-06-27 2000-01-25 Ligand Pharmaceuticals Incorporated Androgen receptor modulator compounds and methods
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US20020173445A1 (en) * 2000-06-28 2002-11-21 Salvati Mark E. Selective androgen receptor modulators and methods for their identification, design and use
US20040077606A1 (en) * 2000-06-28 2004-04-22 Salvati Mark E. Fused cyclic modulators of nuclear hormone receptor function
US20030181728A1 (en) * 2001-12-19 2003-09-25 Salvati Mark E. Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function
US20040019063A1 (en) * 2002-05-17 2004-01-29 Chongqing Sun Bicyclic modulators of androgen receptor function
US20040181064A1 (en) * 2002-05-17 2004-09-16 Chong-Qing Sun Bicyclic modulators of androgen receptor function

Cited By (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050282813A1 (en) * 2000-06-28 2005-12-22 Salvati Mark E Fused cyclic modulators of nuclear hormone receptor function
US20040077606A1 (en) * 2000-06-28 2004-04-22 Salvati Mark E. Fused cyclic modulators of nuclear hormone receptor function
US7001911B2 (en) 2000-06-28 2006-02-21 Bristol-Myers Squibb Company Fused cyclic modulators of nuclear hormone receptor function
US7655689B2 (en) 2000-06-28 2010-02-02 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US7432267B2 (en) 2000-06-28 2008-10-07 Bristol-Myers Squibb Comapny Fused cyclic modulators of nuclear hormone receptor function
US20060264459A1 (en) * 2000-06-28 2006-11-23 Salvati Mark E Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20080214643A1 (en) * 2000-09-19 2008-09-04 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20050192253A1 (en) * 2000-09-19 2005-09-01 Salvati Mark E. Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20050272799A1 (en) * 2000-09-19 2005-12-08 Salvati Mark E Fused Heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20060223832A1 (en) * 2001-06-20 2006-10-05 Salvati Mark E Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US7759371B2 (en) 2001-12-11 2010-07-20 Kyowa Hakko Kinn Co., Ltd. Thiadiazoline derivative
US20100240716A1 (en) * 2001-12-11 2010-09-23 Kyowa Hakko Kirin Co., Ltd. Thiadiazoline derivative
US7902234B2 (en) 2001-12-11 2011-03-08 Kyowa Hakko Kirin Co., Ltd. Thiadiazoline derivative
US20080207706A1 (en) * 2001-12-11 2008-08-28 Kyowa Hakko Kogyo Co., Ltd Thiadiazoline derivative
US20060020002A1 (en) * 2001-12-19 2006-01-26 Salvati Mark E Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function
US20050187273A1 (en) * 2001-12-19 2005-08-25 Salvati Mark E. Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function
US8318782B2 (en) 2003-04-18 2012-11-27 Kyowa Hakko Kirin Co., Ltd. Mitotic kinesin inhibitor
US20070155804A1 (en) * 2003-04-18 2007-07-05 Kyowa Hakko Kogyo Co., Ltd. Of Tokyo, Japan Fuji Photo Film Co., Ltd. Kanagawa, Japan Mitotic kinesin inhibitor
US7851635B2 (en) 2003-04-18 2010-12-14 Kyowa Hakko Kirin Co., Ltd. Mitotic kinesin inhibitor
US20070276017A1 (en) * 2003-06-10 2007-11-29 Chikara Murakata Thiadiazoline Derivative
US20070112044A1 (en) * 2003-10-10 2007-05-17 Kyowa Hakko Kogyo Co., Ltd. Thiadiazoline derivative
US20060178383A1 (en) * 2004-08-06 2006-08-10 Bischoff Francois P Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)
US8426429B2 (en) 2004-08-06 2013-04-23 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
US8383637B2 (en) 2004-08-06 2013-02-26 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
US8436006B2 (en) 2004-08-06 2013-05-07 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
US20060079686A1 (en) * 2004-08-06 2006-04-13 Ellen Baxter Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)
US20060079687A1 (en) * 2004-08-06 2006-04-13 Ellen Baxter Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)
US20080194653A1 (en) * 2005-03-22 2008-08-14 Kyowa Hakko Kogyo Co., Ltd. Therapeutic Agent For Solid Tumor
US20080262049A1 (en) * 2005-03-22 2008-10-23 Kyowa Hakko Kogyo Co., Ltd. Therapeutic Agent for Hematopoietic Tumor
US20100029625A1 (en) * 2005-06-24 2010-02-04 Kyowa Hakko Kirin Co., Ltd. Therapeutic Agent for Restenosis
US7910611B2 (en) 2005-06-24 2011-03-22 Kyowa Hakko Kirin Co., Ltd. Therapeutic agent for restenosis
US7776882B2 (en) * 2006-02-06 2010-08-17 Baxter Ellen W 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of β-secretase (BACE)
US20070232642A1 (en) * 2006-02-06 2007-10-04 Baxter Ellen W 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US20070232630A1 (en) * 2006-02-06 2007-10-04 Baxter Ellen W MACROCYCLE DERIVATIVES USEFUL AS INHIBITORS OF beta-SECRETASE (BACE)
US7868022B2 (en) 2006-02-06 2011-01-11 Janssen Pharmaceutica Nv 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE)
US7932261B2 (en) 2006-02-06 2011-04-26 Janssen Pharmaceutica Nv Macrocycle derivatives useful as inhibitors of β-secretase (BACE)
US20080194624A1 (en) * 2006-02-06 2008-08-14 Ellen Baxter 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US20090227627A1 (en) * 2008-01-28 2009-09-10 Ellen Baxter 6-substituted-thio-2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US8076358B2 (en) 2008-01-28 2011-12-13 Janssen Pharmaceutica Nv 6-substituted-thio-2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE)
US7786116B2 (en) 2008-01-29 2010-08-31 Janssen Pharmaceutica N.V. 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE)
US20090227581A1 (en) * 2008-01-29 2009-09-10 Ellen Baxter 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
US9248136B2 (en) 2011-11-23 2016-02-02 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US8633178B2 (en) 2011-11-23 2014-01-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8846649B2 (en) 2011-11-23 2014-09-30 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8846648B2 (en) 2011-11-23 2014-09-30 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11793819B2 (en) 2011-11-23 2023-10-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11103516B2 (en) 2011-11-23 2021-08-31 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8987237B2 (en) 2011-11-23 2015-03-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10675288B2 (en) 2011-11-23 2020-06-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9012434B2 (en) 2012-06-18 2015-04-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11865179B2 (en) 2012-06-18 2024-01-09 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US8933059B2 (en) 2012-06-18 2015-01-13 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11529360B2 (en) 2012-06-18 2022-12-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US11166963B2 (en) 2012-06-18 2021-11-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11110099B2 (en) 2012-06-18 2021-09-07 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8987238B2 (en) 2012-06-18 2015-03-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11033626B2 (en) 2012-06-18 2021-06-15 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9006222B2 (en) 2012-06-18 2015-04-14 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10639375B2 (en) 2012-06-18 2020-05-05 Therapeuticsmd, Inc. Progesterone formulations
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11622933B2 (en) 2012-12-21 2023-04-11 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11497709B2 (en) 2012-12-21 2022-11-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11351182B2 (en) 2012-12-21 2022-06-07 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10835487B2 (en) 2012-12-21 2020-11-17 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10888516B2 (en) 2012-12-21 2021-01-12 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11304959B2 (en) 2012-12-21 2022-04-19 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11065197B2 (en) 2012-12-21 2021-07-20 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11241445B2 (en) 2012-12-21 2022-02-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11123283B2 (en) 2012-12-21 2021-09-21 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11116717B2 (en) 2012-12-21 2021-09-14 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11103513B2 (en) 2014-05-22 2021-08-31 TherapeuticsMD Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10668082B2 (en) 2014-10-22 2020-06-02 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10398708B2 (en) 2014-10-22 2019-09-03 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10912783B2 (en) 2015-07-23 2021-02-09 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10532059B2 (en) 2016-04-01 2020-01-14 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
CN106349160B (zh) * 2016-08-05 2019-07-26 浙江工业大学 一种8-氨基喹啉衍生物及其制备与应用
CN106349160A (zh) * 2016-08-05 2017-01-25 浙江工业大学 一种8‑氨基喹啉衍生物及其制备与应用
CN107954992A (zh) * 2017-12-15 2018-04-24 田元强 吡咯二酮衍生物及其在小菜蛾和桃蚜防治中的应用
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations
CN113620969A (zh) * 2020-05-07 2021-11-09 贵州医科大学 带桥环的环己烷二羧酸衍生物及其药物组合物和应用

Also Published As

Publication number Publication date
CA2439265A1 (en) 2002-09-06
US7655688B2 (en) 2010-02-02
WO2002067939A1 (en) 2002-09-06
EP1379249A1 (en) 2004-01-14
EP1379249A4 (en) 2008-01-09
HUP0304055A2 (hu) 2004-04-28
JP2004523558A (ja) 2004-08-05
US20060111424A1 (en) 2006-05-25

Similar Documents

Publication Publication Date Title
US7655688B2 (en) Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US7291637B2 (en) Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function
AU2001269943B2 (en) Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US7235563B2 (en) Spirocyclic compounds useful as modulators of nuclear hormone receptor function
EP1458723B1 (en) Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US7550458B2 (en) Tricycloundecane compounds useful as modulators of nuclear hormone receptor function
US20080214643A1 (en) Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
AU2001269943A1 (en) Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US6953679B2 (en) Method for the preparation of fused heterocyclic succinimide compounds and analogs thereof
AU2002250163A1 (en) Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
RU2298554C2 (ru) Конденсированные гетероциклические сукцинимидные соединения

Legal Events

Date Code Title Description
AS Assignment

Owner name: BRISTOL-MYERS SQUIBB COMPANY, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SALVATI, MARK E.;ATTAR, RICARDO M.;GOTTARDIS, MARCO M.;AND OTHERS;REEL/FRAME:012670/0391;SIGNING DATES FROM 20020325 TO 20020425

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE