EP1175413A1 - 2,1-benzisothiazoline 2,2-dioxydes - Google Patents

2,1-benzisothiazoline 2,2-dioxydes

Info

Publication number
EP1175413A1
EP1175413A1 EP00930286A EP00930286A EP1175413A1 EP 1175413 A1 EP1175413 A1 EP 1175413A1 EP 00930286 A EP00930286 A EP 00930286A EP 00930286 A EP00930286 A EP 00930286A EP 1175413 A1 EP1175413 A1 EP 1175413A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
alkoxy
hydrogen
ammoalkyl
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.)
Withdrawn
Application number
EP00930286A
Other languages
German (de)
English (en)
Inventor
Mark A. Collins
Valerie A. Mackner
Lin Zhi
Todd K. Jones
Christopher M. Tegley
Jay E. Wrobel
James P. Edwards
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.)
Wyeth LLC
Ligand Pharmaceuticals Inc
Original Assignee
Ligand Pharmaceuticals Inc
American Home Products Corp
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
Priority claimed from US09/552,630 external-priority patent/US6339098B1/en
Application filed by Ligand Pharmaceuticals Inc, American Home Products Corp filed Critical Ligand Pharmaceuticals Inc
Publication of EP1175413A1 publication Critical patent/EP1175413A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Intracellular receptors form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R M Evans, Science 240, 889, 1988)
  • the steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR)
  • PR progesterone receptor
  • ER estrogen receptor
  • AR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • the natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as hgands
  • a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/hgand complex
  • This complex binds to
  • a compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist PR agonists (natural and synthetic) are known to play an important role in the health of women PR agonists are used in birth control formulations, typically in the presence of an ER agonist ER agonists are used to treat the symptoms of menopause, but have been associated with a probferative effect on the uterus which can lead to an increased risk of uterine cancers
  • Co-administration of a PR agonist reduces or ablates that ⁇ sk
  • PR antagonists may also be used in contraception In this context they may be administered alone (Ulmann et al, Ann N Y Acad Sci 261, 248, 1995), in combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 95-9619997 Al 960704) PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Hor Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers.
  • hormone dependent breast cancers Hor Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis
  • PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al, J. Clin. Endo. Metab. 76, 513, 1993) and endometriosis (Kettel et al, Fertility and Sterility 56, 402, 1991).
  • PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136).
  • PR antagonists such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al, Ann. N. Y. Acad. Sci. 761, 224, 1995).
  • Kamireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 9533746).
  • This invention provides progesterone receptor antagonists of Formula 1 having the structure
  • Ri, and R 2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl, or Ri and R2 are taken together form a ⁇ ng and together contain -CH 2 (CH 2 ) n CH 2 - ,
  • Ri and R 2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end,
  • R 3 is hydrogen, hydroxyl, NH 2 , alkyl, substituted alkyl, alkenyl, alkynyl, substituted or,
  • R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl
  • R 4 is hydrogen, halogen, -CN, -NH 2 , alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl
  • R 5 is a t ⁇ substituted phenyl ⁇ ng having the structure
  • X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl.
  • R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
  • R c is hydrogen, alkyl, or substituted alkyl;
  • Y and Z are each, independently, hydrogen, halogen, -CN, -NO 2 , alkoxy, alkyl, or thioalkyl; or
  • R 5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO alkyl, alkoxy, aminoalkyl, COR D , and NR E COR D ;
  • R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted arninoalkyl
  • R E is hydrogen, alkyl, or substituted alkyl
  • R 6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR 6 is bonded to a ring double bond; or pharmaceutically acceptable salt thereof, which are useful for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy
  • Prefe ⁇ ed compounds of this invention are those having the structure:
  • X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO , perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
  • Y and Z are each, independently, hydrogen, halogen, -CN, -NO 2 , alkoxy, alkyl, or thioalkyl; or R 5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR 6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO 2 , alkyl, or alkoxy; R 6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR 6 is bonded to a ring double bond; or pharmaceutically acceptable salt thereof. More preferred compounds of this invention are those having the structure
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 5 is a disubstituted phenyl ⁇ ng having the structure
  • X is halogen, -CN, or -NO 2 ,
  • Y is hydrogen, halogen, -CN, -NO 2 , alkoxy, alkyl, or thioalkyl
  • R 5 is a five or six membered heteroaryl ⁇ ng containing a heteroatom selected from the group consisting of O, S, and NR 6 with said ⁇ ng carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NO ,
  • R 6 is hydrogen, or is absent when the nitrogen of NR 6 is bonded to a ⁇ ng double bond, or pharmaceutically acceptable salt thereof
  • the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmet ⁇ c centers and may thus give ⁇ se to optical isomers and diastereoisomers While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers, as well as the racemic and resolved, enantiome ⁇ cally pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof
  • alkyl is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms
  • alkenyl includes both straight- and branched-chain alkyl group of 2-6 carbon atoms containing at least one carbon-carbon double bond
  • alkynyl includes both straight- and branched-chain alkyl group of 2-6 carbon atoms with at least one carbon-carbon t ⁇ ple bond
  • substituted alkyl refers to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NO , amino, aryl, heterocycbc, substituted aryl, substituted heterocycbc, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio
  • substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety
  • aryl is used herein to refer to an aromatic system of 6-14 carbon atoms, which may be a single ⁇ ng or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system Prefe ⁇ ed
  • heterocycbc is used herein to describe a stable 4-14 membered monocycbc or multicycbc heterocycbc ⁇ ng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms
  • the N and S atoms may be oxidized, as an N-oxide, sulfoxide, or sulfone
  • the heterocycbc ring also includes any multicycbc ⁇ ng in which any of above defined heterocycbc ⁇ ngs is fused to an aryl ⁇ ng
  • the heterocycbc ⁇ ng may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable
  • Such heterocycbc groups include, for example, tetrahydrofuran, pipe ⁇ dinyl, p ⁇ erazinyl, 2-oxop ⁇ pe ⁇ d ⁇ nyl,
  • substituted heterocycbc is used herein to desc ⁇ be a heterocycbc having one or more substituents selected from the group which includes halogen, CN,
  • thioalkyl is used herein to refer to the SR group, where R is alkyl or substituted alkyl
  • alkoxy is used herein to refer to the OR group, where R is alkyl or substituted alkyl
  • aryloxy is used herein to refer to the OR group, where R is aryl or substituted aryl
  • alkylcarbonyl is used herein to refer to the RCO group, where R is alkyl or substituted alkyl
  • alkylcarboxy is used herein to refer to the COOR group, where R is alkyl or substituted alkyl This term is also referred to as alkoxycarbonyl
  • aminoalkyl refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups may be either same or different and the point of attachment is on the nitrogen atom
  • salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, cit ⁇ c, tarta ⁇ c, succinic, fumaric, maleic, malonic, mandebc, mabc, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfu ⁇ c, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfomc, camphorsulfonic, and similarly known acceptable acids
  • Salts may also be formed from inorganic bases, preferably alkab metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and t ⁇ methylammonium, mono-, di- and triethylammonium, mono-, di- and t ⁇ propyl- ammonium (iso and normal), eth
  • the compounds of this invention were be prepared according to the following schemes from commercially available starting mate ⁇ als or starting mate ⁇ als which can be prepared using bterature procedures These schemes show the preparation of representative compounds of this invention
  • the protected sultam 7 next is treated with a strong organo-metalhc base (e g , butyl bthium, bthium dusopropylamide, potassium hexamethyldisilylazide) in an inert solvent (e g , THF, diethyl ether) under nitrogen at reduced temperature (ca -20 °C) (Kende et al, Synth Commun 12, 1, 1982)
  • the resulting di-anion then is treated with excess electrophile such as an alkyl habde, preferably the iodide If Ri, and R 2 are to be joined such as the product contains a spirocycle at position 3, then the electrophile should be bifunctional, I e , a diiodide
  • bromination of the sultam 8 proceeds regioselectively at room temperature with bromine m acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium a
  • R,-X leaving group, e g , iodide
  • the resultant mono-alkylated compound may be then isolated and re-subjected to the reaction conditions using R 2 -X, or alternatively used in situ for the second alkylation with R 2 -X
  • bromide 9 may be converted to an aryl boronic acid via standard procedures (treatment with n-butylbthium followed by addition of t ⁇ methyl borate and subsequent boronic ester hydrolysis) that will then undergo the range of previously desc ⁇ bed coupling procedures with a suitable aryl bromide
  • the antiprogestational activity of the compounds of this invention was demonstrated in an in vitro standard pharmacological test procedure which evaluated the antiprogestational potency of a representative compound of this invention by measuring its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids
  • the procedure used and results obtained are desc ⁇ bed in Example 2 below
  • the results obtained in this standard pharmacological test procedure demonstrate that the compounds of this invention are progestational antagonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combmed with an estrogen), in the treatment of endomet ⁇ osis, luteal phase defects, benign breast and prostatic diseases and prostatic, breast, ova ⁇ an, uterine and endomet ⁇ al cancers
  • the compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or androgens
  • the compounds of this invention can be formulated neat or with a pharmaceutical earner for administration, the proportion of which is determmed by the solubibty and chemical nature of the compound, chosen route of administration and standard pharmacological practice
  • the pharmaceutical earner may be solid or liquid
  • a sobd earner can include one or more substances which may also act as flavoring agents, lubncants, solubibzers, suspending agents, fillers, gbdants, compression aids, binders or tablet-disintegrating agents, it can also be an encapsulating matenal
  • the earner is a finely divided sobd which is in admixture with the finely divided active ingredient
  • the active ingredient is mixed with a earner having the necessary compression properties in suitable proportions and compacted in the shape and size desired
  • the powders and tablets preferably contain up to 99% of the active ingredient
  • Suitable solid earners mclude, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl ceUulose, polyvmylpyrrohdine, low melting waxes and ion exchange resins
  • Liquid earners are used in preparing solutions, suspensions
  • Liquid pharmaceutical compositions which are ste ⁇ le solutions or suspensions can be utibzed by, for example, intramuscular, intrapentoneal or subcutaneous injection Ste ⁇ le solutions can also be administered intravenously
  • the compounds of this invention can also be administered orally either m bquid or sobd composition form
  • the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utibzed m the form of an aerosol
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a earner that is inert to the active compound, is non toxic to the skin, and aUows debvery of the agent for systemic absorption into the blood stream via the skin
  • the earner may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices
  • the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type Pastes comp ⁇ sed of absorptive powders dispersed in petroleum
  • the dosage requirements vary with the particular compositions employed, the route of administration, the seventy of the symptoms presented and the particular subject being treated Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0 02 ⁇ g/kg - 750 ⁇ g/kg Treatment will generally be initiated with small dosages less than the optimum dose of the compound Thereafter the dosage is mcreased until the optimum effect under the circumstances is reached, precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on expenence with the individual subject treated
  • the pharmaceutical composition is in unit dosage form, e g as tablets or capsules
  • the composition is sub-divided m unit dose containing approp ⁇ ate quantities of the active mgredient
  • the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled synnges or sachets containmg bquids
  • the unit dosage form can be, for example, a
  • Growth medium DMEM (BioWhittaker) containmg 10% (v/v) fetal bovine serum (heat mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml penicillin. lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL)
  • Expenmental medium DMEM (BioWhittaker), phenol red-free, containmg 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) Test Procedure
  • Example 1 had an IC 50 of 900 nM The IC 50 is the concentration of test compound that gives half-maximal decrease in 3 nM progesterone mduced PRE-luciferase activity

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

La présente invention concerne un antagoniste du récepteur de progestérone de formule (1) dans laquelle R1, et R2 représentent individuellement hydrogène, alky, alkyle substitué, hydroxy, alcoxy, alcoxy substitué, aryle, aryle substitué, hétéroaryle, hétéroaryle substitué, arylalkyle, hétéroarylalkyle, et alcynyle; ou R1 et R2 pris ensemble contiennent -CH2(CH2)nCH2-, -CH2CH2CMe2CH2-CH2-, -O(CH2)pCH2-, O(CH2)qO-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; ou R1 et R2 représentent une double liaison, cette double liaison ayant deux groupes méthyle liés à l'extrémité terminale, un groupe cycloalkyle lié à l'extrémité terminale, un oxygène lié à l'extrémité terminale, ou un cycloéther lié à l'extrémité terminale; R5 représente un cycle phénylique trisubstitué de structure (2), ou R5 représente un cycle hétéroaryle à 5 ou 6 éléments contenant 1, 2, ou 3 hétéroatomes sélectionnés dans le groupe constitué par O, S, SO¿2? et NR?6¿, ou un sel de celui-ci acceptable sur le plan pharmaceutique.
EP00930286A 1999-05-04 2000-05-01 2,1-benzisothiazoline 2,2-dioxydes Withdrawn EP1175413A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US18303999P 1999-05-04 1999-05-04
US183039P 1999-05-04
US09/552,630 US6339098B1 (en) 1999-05-04 2000-04-19 2,1-benzisothiazoline 2,2-dioxides
US552630 2000-04-19
PCT/US2000/011823 WO2000066574A1 (fr) 1999-05-04 2000-05-01 2,1-benzisothiazoline 2,2-dioxydes

Publications (1)

Publication Number Publication Date
EP1175413A1 true EP1175413A1 (fr) 2002-01-30

Family

ID=26878685

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00930286A Withdrawn EP1175413A1 (fr) 1999-05-04 2000-05-01 2,1-benzisothiazoline 2,2-dioxydes

Country Status (6)

Country Link
EP (1) EP1175413A1 (fr)
JP (1) JP2002543195A (fr)
CN (1) CN1349518A (fr)
AU (1) AU4813800A (fr)
CA (1) CA2371758A1 (fr)
MX (1) MXPA01011292A (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0066574A1 *

Also Published As

Publication number Publication date
CN1349518A (zh) 2002-05-15
JP2002543195A (ja) 2002-12-17
CA2371758A1 (fr) 2000-11-09
AU4813800A (en) 2000-11-17
MXPA01011292A (es) 2003-07-14

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