EP1144396A2 - Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents - Google Patents

Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents

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Publication number
EP1144396A2
EP1144396A2 EP99968883A EP99968883A EP1144396A2 EP 1144396 A2 EP1144396 A2 EP 1144396A2 EP 99968883 A EP99968883 A EP 99968883A EP 99968883 A EP99968883 A EP 99968883A EP 1144396 A2 EP1144396 A2 EP 1144396A2
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EP
European Patent Office
Prior art keywords
carbons
methyl
alkyl
thiazolidine
nitrophenylimino
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Withdrawn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
EP99968883A
Other languages
German (de)
English (en)
French (fr)
Inventor
Brian R. Dixon
Cedo M. Bagi
Catherine R. Brennen
David R. Brittelli
William H. Bullock
Jinshan Chen
William L. Collibee
Robert Dally
Jeffrey S. Johnson
Harold C. E. Kluender
William F. Lathrop
Peiying Liu
Carol Ann Mase
Aniko M. Redman
William J. Scott
Klaus Urbahns
Donald J. Wolanin
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Bayer AG
Bayer Corp
Original Assignee
Bayer AG
Bayer Corp
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Publication of EP1144396A2 publication Critical patent/EP1144396A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

Definitions

  • FIELD This invention relates to heterocyclic pharmaceuticals, and more particularly, to 2-arylimino heterocycles, pharmaceutical compositions containing them, and their use in modulating progesterone receptor mediated processes.
  • BACKGROUND An agent which binds to the progesterone receptor may be employed for a wide variety of indications, including those shown in the lettered paragraphs below: Al) to enhance bone formation in bone weakening diseases, for the prevention of and/or treatment of osteopenia or osteoporosis (Manzi, et al., J. Soc. Gynecol. Invest., I, 302 (1994); Scheven, et al., Biochem. Biophys. Res.
  • progesterone or progestins alone or in combination with estrogens are clinically indicated: for contraception (Merck Manual; Merck & Co. (1992)); for treatment of gastrointestional bleeding due to arteriovenous malformations (Merck Manual; Merck & Co. (1992)); for treatment of recurrent metatarsal stress fractures complicated by oligiomenorrhea or amenorrhea (Merck Manual; Merck & Co. (1992)); for treatment of premenstral syndrome (PMS, premenstral tension; Merck Manual; Merck & Co.
  • medroxyprogesterone, a progestin, alone or in combination with estrogens is indicated for prevention of osteoporosis, treatment of vulvar and/or vaginal atrophy, treatment of moderate to severe vasomotor symptoms associated with menopause, treatment of secondary amenorrehea, treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, prevention of pregnancy, or as adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma (Merck Manual; Merck & Co. (1998)).
  • This invention provides nonsteroidal 2-arylimino- and 2-heteroarylimino- heterocyclic compounds which have affinity for the progesterone receptor, and therefore can act as progestins and/or antiprogestins thus modulating progesterone receptor mediated processes.
  • This invention relates to compounds having the formula (I)
  • R is aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene;
  • R' is alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; heterocycloalkyl of 4 - 7 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, O, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of
  • R 5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and
  • X is O or S(O) y ; wherein y is O, l, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R 2 , R 3 , and R 4 ; T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons;
  • R 6 is H or alkyl of 1 - 5 carbons
  • R 7 is H or alkyl of 1 - 5 carbons
  • R 9 is H, halogen, or alkyl of 1 - 4 carbons; C(O)NHC(O) , the carbons being connected to adjacent positions on
  • T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; CO 2 R 5 ; CO 2 H; C(O)N(R 6 )(R 7 );
  • G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;
  • Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; haloalkyl of 1 - 4 carbons; cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbon
  • the invention also relates to pharmaceutical compositions which include a compound of formula (I) as disclosed above, plus a pharmaceutically acceptable carrier.
  • the compounds of this invention As a result of their affinity for the progesterone receptor and their resultant ability to act as progestins and/or antiprogestins, and thus modulate progesterone receptor mediated processes, the compounds of this invention, as well as certain related compounds of the prior art, are believed to be useful for the purposes listed in the background section.
  • the invention relates further to a method of treating a mammal to achieve an effect, wherein the effect is:
  • cancers including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer
  • R is aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene;
  • R' is alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; heterocycloalkyl of 4 - 7 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, O, and S; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, O, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; R 2
  • X is O or S(O) y ; wherein y is O, l, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R 2 , R 3 , and R 4 ; s represents the number of double bonds in the ring, and is 0, 1, or 2; T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO 2 H; CO 2 R 5 ; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C 6 H 5 ;
  • R 6 is H or alkyl of 1 - 5 carbons; and R 7 is H or alkyl of 1 - 5 carbons; S(O) y R 8 ; wherein y' is 1 or 2; and
  • R 8 is alkyl of 1 - 5 carbons; SO 2 F; CHO; OH; NO 2 ;
  • R 9 is H, halogen, or alkyl of 1 - 4 carbons; C(O)NHC(O) , the carbons being connected to adjacent positions on R; and C(O)C 6 H 4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; t is l - 5; provided that when substituent moiety T is alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO 2 R 5 ; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C 6 H 5 ; C(O)N(R 6 )(R 7 ); S(O) y ,R 8
  • alkyl of 1 - 4 carbons alkenyl of 1 - 4 carbons; cycloalkyl of 3 - 7 carbons; heterocycloalkyl of 3 - 5 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
  • g is 0 - 4, with the exception of halogen, which may be employed up to the perhalo level; provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, heterocycloalkyl of 3 - 5 carbons, cycloalkenyl of 5 - 7 carbons, or heterocycloalkenyl of 4 - 6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons
  • R is preferably phenyl or pyridyl.
  • R 1 is preferably alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings, alkenyl of 2 - 10 carbons, cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings, or alkynyl of 3 - 10 carbons.
  • R 1 is more preferably alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings, alkenyl of 2 - 10 carbons, or cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings.
  • R 2 , R 3 , and R 4 are more preferably H, alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons, alkenyl of 2 - 10 carbons, or cycloalkenyl of 5 - 12 carbons.
  • X is preferably O or S(O) y , wherein y is 0, 1 , or 2.
  • n representing the number of carbons in the ring, is preferably 2 or 3.
  • the subscript p representing the sum of non-H substituents R 2 , R 3 , and R 4 , is preferably 1 or 2.
  • T is a substituent preferably selected from the group consisting of alkyl of 1- 4 carbons, alkoxy of 1 - 4 carbons, alkenyl of 2 - 4 carbons, alkynyl of 2 - 4 carbons, NO 2 , CN, and halogen.
  • T is more preferably alkyl of 1 - 4 carbons, alkenyl of 2 - 4 carbons, NO 2 , CN, or halogen.
  • the subscript t representing the number of substituents T, is 1 - 5, more preferably 1 - 3.
  • the term "secondary substituent” means a substituent on a substituent, not “secondary” as used in defining the degree of substitution at a carbon.
  • haloalkyl and “halocycloalkyl” are employed to refer to groups which may contain halogen atoms in any number up to the per-halo level.
  • G is preferably selected from the group consisting of halogen, OR 5 , alkyl of 1
  • G is more preferably halogen, alkyl of 1 -
  • the subscript g representing the number of substituents G, is 0 - 4, more preferably 0 - 2, with the exception of halogen, which may be employed up to the perhalo level.
  • Q is more preferably alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 8 carbons, alkoxy of 1 - 8 carbons, alkenyl of 2 - 5 carbons, cycloalkenyl of 5 - 8 carbons, or halogen.
  • the present invention also includes pharmaceutically acceptable salts of the compounds of Formula I.
  • suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.
  • pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine,
  • alkaline cations e.g., Li + Na + or K +
  • alkaline earth cations e.g., Mg +2 , Ca +2 or Ba +2
  • the ammonium cation as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such
  • DMAP N.N-dimethylaminopyridine
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • DB ⁇ 1,5- diazabicyclo[4.3.0]non-5-ene
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • the present invention encompasses any racemic or optically active forms of compounds described in Formula I which possess progesterone receptor binding activity.
  • 2-imino-l, 3-thiazolidines and ring expanded homologues of 2-imino- 1 ,3-thiazolidines of the invention are the following:
  • thiazolidin-4-ones of the invention are the following:
  • oxazolidines of the invention are the following:
  • the therapeutic agents of the invention may be employed alone or concurrently with other therapies.
  • the agent when employed as in Al or A2, the agent may be used in combination with a calcium source, vitamin D or analogues of vitamin D, and/or antiresorptive therapies such as estrogen replacement therapy, treatment with a fluoride source, treatment with calcitonin or a calcitonin analogue, or treatment with a bisphosphonate such as alendronate.
  • the agent may be used with therapies such as estrogen replacement therapy.
  • the agent may be used concurrently with therapies such as estrogen replacement therapy and/or a gonadotropin-releasing hormone agonist.
  • the agent When employed as in Gl or G2, the agent may be used concurrently with therapies such as an androgen.
  • the method of the invention is intended to be employed for treatment of progesterone receptor mediated conditions in both humans and other mammals.
  • the compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations.
  • the term 'administered by injection' includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
  • Dermal administration may include topical application or transdermal administration.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients.
  • compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or /j-propyl, 7-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or /j-propyl, 7-hydroxybenzoate
  • coloring agents for example ethyl, or /j-propyl, 7-hydroxybenzoate
  • coloring agents for example ethyl, or /j-propyl, 7-hydroxybenzoate
  • flavoring agents for example ethyl, or /j-propyl, 7-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
  • the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • a thickening agent for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.
  • These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of oil- in-water emulsions.
  • the oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug.
  • suppositories for rectal or vaginal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO
  • a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
  • a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
  • Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane.
  • Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones , lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
  • Suitable penetration enhancing materials for transdermal delivery systems include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C 8 -C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C 8 -C 18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, rc-butyl, .sec- butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, di
  • Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether.
  • Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -C 18 fatty alcohols, saturated or unsaturated C 8 -C 18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
  • Suitable binding materials for transdermal delivery systems include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers.
  • Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of Formula I may be prepared by use of known chemical reactions and procedures, from known compounds (or from starting materials which, in turn, are producible from known compounds) through the preparative methods shown below as well as by other reactions and procedures known to the skilled in the art. Nevertheless, the following general preparative methods are presented to aid practitioners in synthesizing the compounds of the invention, with more detailed particular examples being presented in the experimental section. The examples are for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any way.
  • Aryl amines, aryl isocyanates, aryl isothiocyanates, unsymmetrical aryl thioureas, aryl isocyanate dichlorides and 2-arylimino- 1,3 -heterocycles may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985)).
  • aryl isocyanates (2) are available from the reaction of phosgene, or a phosgene equivalent, such as carbonyl diimidazole, diphosgene or triphosgene
  • aryl isothiocyanates (3) are available from reaction of an aryl amine with thiophosgene or a thiophosgene equivalent, such as thiocarbonyl diimidazole (Scheme I).
  • aryl isocyanates and aryl isothiocyanates are commercially available. Reaction of an aryl isothiocyanate with a primary amine then affords thiourea 4 (Hahn et al. Han'guk Nonghwa Hakhoechi 1991,40, 139; D ⁇ rr US Patent 4,079,144; Enders US Patent 4,148,799).
  • thioureas react with ⁇ -haloketones, e.g. ⁇ - bromoketone 5, to afford, after dehydration, the thiazoline (6) (Hahn et al. Han'guk Nonghwa Hakhoechi 1991,40, 139; DUrr US Patent 4,079,144; Enders US Patent 4,148,799).
  • thioureas react with ⁇ -haloacid halides (Giri et al. Asian J. Chem. 1992, 4, 785; Lakhan et al. Agric. Biol Chem. 1982,46, 557), ⁇ -haloacids (Dogan et al. Spectrosc. Lett. 1983, 16, 499; Seada et al. Indian J. Heterocycl. Chem. 1993, 3, 81), and ⁇ -haloesters (Seada et al. Indian J. Heterocycl. Chem. 1993, 5, 81) to afford 4-thiazolidinones (10).
  • Aryl isothiocyanates (3) also react with allylamines (Tsoi et al. Zh. Org.
  • Aryl isothiocyanates may also be reacted with hydroxylamines (17) to form N-hydroxyalkylthiourea 18 (Scheme V).
  • Treatment of the thiourea with acid then leads to 2-imino-l,3-heterocycle 19 (Jen et al. J.Med. Chem. 1975, 18, 90; Tyukhteneva et al. Khim. Geterotsikl Soedin. 1985, 12, 1629; Olszenko-Piontkowa et al. Org. Prep. Proced. Int. 11971, 3, 27).
  • Chloroalkyl isothiocyanates have been reported to react with arylamines to afford the corresponding sulfur 2-phenylimino-l,3-heterocycle (Sagner et al. US Patent 3,651,053; Ibid US Patent 3,737,536).
  • Aryl amines react with a formylating source, such as formic acetic anhydride, to form formanilide 25, which may then be oxidatively converted to the aryl isocyanide dichloride (Ferchland et al. DE 3,134,134; for a review, see: Kuehle et al. Angew. Chem. 1967, 79, 663).
  • Aryl isocyanide dichlorides (26) react with hydroxylamines (27) to give oxygen-containing 2-phenylimino-l,3-heterocycle 30 (Wollweber US Patent 3,787,575; Ibid US Patent 3,686,199) and with hydroxylamide 28 to give thiazolidinone 31.
  • aryl isoyanide dichlorides have been shown to react with aminomercaptans (29) to give the sulfur-containing 2- phenylimino- 1,3 -heterocycle 32 (Thibault French Patent 1,510,015).
  • sulfur-containing 2-imino-l,3- heterocycles may be oxidized to the sulfoxide or sulfone (Chizhevskayaet al. Khim. Geterotsikl. Soedin. 1971, 96; Pandey et al. J. Indian Chem. Soc. 1972, 49, 171).
  • the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg.
  • Bulb-to-bulb concentrations were conducted using an Aldrich Kugelrohr apparatus, and in these cases temperatures refer to oven temperatures. All temperatures are reported uncorrected in degrees Celcius (°C). Unless otherwise indicated, all parts and percentages are by volume.
  • Thin-layer chromatography was performed on Whatman ® pre-coated glass- backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM
  • Chemical ionization mass spectra were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lxlO "4 torr to 2.5x10 " “ torr).
  • the direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.
  • HPLC - electrospray mass spectra were obtained using a Hewlett- Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source.
  • GC-MS Gas chromatography - ion selective mass spectra
  • A4a General method for the synthesis of nitroanilines from anilines. Synthesis of 2,3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroaniline.
  • 2-Aminonorbornane-2-carboxylic acid was converted into 2-amino-2- (hydroxymethyl)norbornane as a diastereomeric mixture in a manner analogous to Method Bla.
  • a solution of the amino alcohol (0.31 g, 2.16 mmol) and isobutyl bromide (0.23 ml, 2.16 ml) in DMF (3 mL) was heated at 90 °C for 92 h, then cooled to room temp, and partitioned between EtOAc (100 mL) and a saturated NaHCO 3 solution (100 mL).
  • 1,2-dichloroethane was added isobutyraldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol).
  • the reaction mixture was stirred at room temp, for 24 h, then partitioned between Et 2 O (100 mL) and a saturated NaHCO 3 solution (100 mL).
  • the organic layer was washed with a saturated NaHCO 3 solution (3x100 mL), dried (MgSO 4 ), and treated with a IM HCl solution in ether (25 mL).
  • Step 2 To a solution of LiAlH 4 (0.93 g, 24.4 mmol) and A1C1 3 (3.24 g, 24.4 mmol) in THF at 4 °C was added dropwise a solution of 14-aza-7- oxadispiro[4.2.5.1]tetradecane (2.38 g, 12,2 mmol) in THF (15 mL). The resulting mixture was warmed to 20 °C and stirred for 45 min., then cooled to 4 °C. Water (5 mL) was slowly added to quench the reaction and a IN NaOH solution (85 mL) was added to dissolve the resulting solids. The resulting solution was extracted with Et,O (200 mL).
  • Step l A solution of ( 1 S)- 1 -(hydroxymethyl)-3 -methylbutylamine (Method Bib; 152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv.) in toluene (1.5 L) was heated at the reflux temp, until the theoretical amount of water had been collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated by distillation to approximately 700 mL. The resulting mixture was cooled to room temp, and was concentrated under reduced pressure to a constant weight to give
  • Step l A solution of (L)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt (2.15 g, 4.4 mmol) in CH 2 C1 2 (50 mL) was treated with a solution of CH 2 ⁇ 2 in EtjO until a yellow color persisted. The resulting solution was concentrated under reduced pressure.
  • Step l To a solution of N-(tert-butoxycarbonyl)glycine tert-butyl ester (3.97 g, 17.2 mmol) in DMF (70 mL) at 0 °C was added sodium hexamethyldisilazide (3.78 g, 20.6 mmol) and the resulting mixture was stirred for 25 min., then allowed to warm to room temp. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol), stirred at room temp, for 10 min., and diluted with EtOAc (300 mL).
  • N-(tert-butoxycarbonyl)-N-(2-tosyloxy ethyl)- 1 -amino-2-methylprop-2- ene 15 g, 55.7 mmol was cooled to 0 °C and dissolved in TFA (200 mL). The reaction mixture was allowed to warm to room temp., then was concentrated under reduced pressure. The residual oil was crystallized using ⁇ X__0 (500 mL) to afford N-
  • Step 2 A solution of ( S)-3,4-diisobutyl-l,3-thiazolidin-2-thione (5.0 g, 21.6 mmol) in SOCl 2 (31 mL, 0.43 mol) and was heated at 70 °C for 2.5 h, then was cooled to room temp, and concentrated under reduced pressure to afford ( S)-2-chloro-3,4- diisobutyl-4,5-dihydro-l,3-thiazolinium chloride as a semisolid: 'H NMR ⁇ 0.99- 1.10 (m, 12H), 1.59-1.67 (m, IH), 1.72-1.84 (m, IH), 2.00-2.10 (m, IH), 2.17-2.29 (br m, IH), 3.61-3.68 (m, IH), 3.86-3.95 (br m, 2H), 4.50-4.57 (m, IH), 4.97-5.06
  • N-(Hydroxyethyl)-N-isobutylamine was converted into N-(chloroethyl)-N- isobutylammonium chloride in a manner analogous to Method B7c.
  • Method Bla 1 -Amino- l-(hydroxymethyl)cyclohexane (Method Bla) was dissolved in p- dioxane (80 mL) then treated with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield l-isobutyl-2-(2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) R/0.69.
  • N-Isobutyl-l,l-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a.
  • HCl was bubbled into a solution of N-isobutyl-1,1- dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL) until saturation.
  • SOCl 2 (10 mmol) was added to the solution dropwise at room temp., stirred at room temp, for 1 h and at 50 °C, for 1 h.
  • the resulting mixture was concentrated under reduced pressure and the residue was dissolved in CHC1 3 (20 mL).
  • N,N-Dimethylethylenediamine (92 g, 0.023 mol, 0.3 equiv.) was added and the reaction mixture was stirred for 1 h.
  • Silica gel (50 g) was added and the resulting mixture was concentrated under reduced pressure.
  • N-Cyclohexyl-l,l-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a.
  • a solution of 2,6-dichlorophenyl isothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-l,l-dimethyl-2-hydroxyethanamine (l.Og, 6.0 mmol) in CH 2 C1 2 (10 mL) was stirred for 20 h at room temp.
  • the resulting mixture was concentrated under reduced pressure, then treated with a 33% HCl solution (15 mL).
  • the resulting mixture was heated at the reflux temp, for 1 h, cooled to room temp, and neutralized with a 45% ⁇ aOH solution.
  • the product was converted into the HCl salt by dissolving the free base (5 mmol) in Et 2 O (50 mL) and treating this solution with a 2 ⁇ ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et 2 O (25 mL) followed by EtOAc (25 mL).
  • 1,3-thiazolidine (Method Clc; 0.050 g, 0.16 mmol) in DMF (1.0 mL) was added NaH (0.0045 g, 1.1 equiv.), and the resulting mixture was stirred at room temp, for 5 min. Isobutyl bromide (0.053 mL, 3 equiv.) was then added and the resulting mixture was stirred at 98 °C for 4 h. The reaction mixture was filtered, then concentrated under reduced pressure.
  • 2-(2-Methyl-4-nitrophenylimino)-l, 3-thiazolidine was prepared in a manner analogous to that described in method C2a and was alkylated with l-bromo-3,3- dimethyl-2-butanone in a manner analogous to that described in Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-oxobutyl)-l,3-thiazolidine.
  • Step l To a solution of (45)-2-(4-methoxycarbonyl-2-methylphenylimino)-3,4- diisobutyl-1, 3-thiazolidine (prepared in a manner analogous to that described in Method D2a; 0.035 g, 0.097 mmol) in a mixture of MeOH (1.5 mL) and H 2 O (1.5 mL) was added LiOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d at room temp., then was concentrated under reduced pressure. The residue was adjusted to pH 1 with a 1% HCl solution, then extracted with EtOAc (4x10 mL).
  • D12b General methods for the chain homologation of aldehydes or ketones. Synthesis of 2-(2-ethyl-4-((l_ ⁇ )-2-nitrovinyl)phenylimino)-l-cyclopentyl- 3-thia-l-azaspiro[4.4]nonane.
  • N-Chloroethyl-N'-isobutylammonuim chloride (prepared as described in Method B7c) was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to method Cld to give 2-(2-methoxy-4-nitrophenylimino)-3 -isobutyl- 1, 3-thiazolidine.
  • N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method B7c) was reacted with 4-cyanophenyl isothiocyanate according to method Cld to give 2-(4-cyanophenylimino)-3 -isobutyl- 1 ,3 -thiazolidine .
  • N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method B7c) was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to method Cld to give 2-(4-cyano-2-ethylphenylimino)-3 -isobutyl- 1, 3-thiazolidine.
  • N-Chloroethyl-N '-isobutylammonium chloride (prepared as described in Method B7c) was reacted with 4-chloro-2-(trifluoromethyl)phenyl isothiocyanate according to method Cld to give 2-(4-chloro-2-(trifluoromethyl)phenylimino)-3-isobutyl-l,3- thiazolidine.
  • N-(2-Hydroxyethyl)-N-(2-methylbutyl)amine was reacted with SOCl 2 according to Method B7a to give N-(2-chloroethyl)-N-(2-methylbutyl)ammonium chloride.
  • the chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-l- butyl)-l ,3-thiazolidine.
  • 2- oroet y ammon um c or e ntry 1 was reacte w t -met y - -n trop eny isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 4-bromobut-l-ene according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(but-l-en-4-yl)-l,3-thiazolidine.
  • 3-Pentylamine was converted to N-(2-hydroxyethyl)-N-(3-pentyl)amine according to Method B5a.
  • the amine was reacted with SOCl 2 according to Method B7a to give N-(2-chloroethyl)-N-(3-pentyl)ammonium chloride.
  • the chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give to give 2-(2-methyl-4-nitrophenylimino)-3-(3-pentyl)-l, 3-thiazolidine.
  • Cyclohex-2-en-l-one was reduced according to Method B2b, Step 1 to afford cyclohex-2-en-l-ol.
  • the alcohol was converted to the 3-bromo-l-cyclohexene according to Method B2b, Step 2.
  • the halide was converted to N-(cyclohex-2-en-l- yl)-N-(2-hydroxyethyl)amine according to Method B2b, Step 3.
  • the alcohol was reacted with SOCl 2 according to Method B7a to afford N-(cyclohex-2-en-l-yl)-N-(2- chloroethyl)ammmonium chloride.
  • N-(2-Hydroxyethyl)aniline was reacted with SOCl 2 according to Method B7a to give N-2-chloroethyl)anilinium chloride.
  • the chloroethylamine was reacted with 2- methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl- 4-nitrophenylimino)-3-phenyl-l,3-thiazolidine.
  • 2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3 -dichlorophenylimino)-3 -cyclooctyl- 1 ,3 -thiazolidine.
  • 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3- (cyclopropylmethyl)- 1 ,3-thiazolidine.
  • Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3- (cyclopropylmethyl)- 1 ,3-thiazolidine.
  • 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3- (cyclopropylmethyl)- 1 ,3-thiazolidine.
  • Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-
  • Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3- (cyclobutylmethyl)- 1 ,3-thiazolidine.
  • Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 3-chloro- 2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3- (cyclobutylmethyl)- 1 ,3-thiazolidine.
  • Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclohexylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-
  • N-benzyl-N-(2-hydroxyethyl)amine The alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride.
  • 2-Hydroxyethylamine was reacte w t enzy romi e according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride.
  • 2-Hydroxyethylamine was reacte w t enzy bromi e according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-benzyl-l ,3-thiazolidine.
  • 2-Hydroxyethylamine was reacte w t 4-c orobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 4-cyano-2- ethylphenyl isothiocyanate to give 2-(4-cyano-2-ethylphenylimino)-3-(4- chlorobenzyl)- 1 ,3-thiazolidine.
  • 2-Hydroxyethylamine was reacte w t cyc o eptylmet yl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl)ammonium chloride.
  • the chloroethylamine was reacted with 4- cyanophenyl isothiocyanate to give 2-(4-cyanophenylimino)-3-(cycloheptylmethyl)- 1,3 -thiazolidine.
  • Methyl cyclodo ecanecar oxy ate was re uce accor ng to Method B2b, Step 1 to give cyclododecylmethanol.
  • the alcohol was converted to cyclododecylmethylbromide according to Method B2b, Step 2.
  • the halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N-(2- hydroxyethyl)-N-(cyclododecylmethyl)amine.
  • the alcohol was reacted with SOCl 2 according to Method B7a to give N-(2-chloroethyl)-N-
  • (lS)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib.
  • the 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2.
  • the alcohol was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride as described in Method B7c.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Steroid Compounds (AREA)
EP99968883A 1999-01-14 1999-12-14 Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents Withdrawn EP1144396A2 (en)

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US23190699A 1999-01-14 1999-01-14
US231906 1999-01-14
PCT/US1999/029601 WO2000042031A2 (en) 1999-01-14 1999-12-14 Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents

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SK (1) SK10032001A3 (cs)
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HUP0202460A3 (en) * 1999-08-31 2004-04-28 Schering Ag Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
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JPWO2001072723A1 (ja) * 2000-03-28 2004-01-08 日本曹達株式会社 オキサ（チア）ゾリジン誘導体および抗炎症薬
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EP1465882B1 (en) 2001-12-21 2011-08-24 X-Ceptor Therapeutics, Inc. Hetrocyclic modulators of nuclear receptors
US20060142387A1 (en) * 2003-06-10 2006-06-29 Rodolfo Cadilla Chemical compounds
CN103382158B (zh) * 2013-07-29 2015-11-18 张家港市大伟助剂有限公司 一种2-环戊基氨基乙醇的制备方法
BR112022000188A2 (pt) * 2019-07-10 2022-02-22 Bayer Ag Método para a preparação de 2-(fenilimino)-1,3-tiazolidin-4-onas
CN114507143A (zh) * 2022-02-26 2022-05-17 江苏壹药新材料有限公司 一种2-乙基-1-氟-4-硝基苯的合成方法
CN114671828B (zh) * 2022-04-28 2024-05-31 蔚林新材料科技股份有限公司 一种3-甲基-2-噻唑硫酮的制备方法
CN114957288B (zh) * 2022-06-07 2024-02-13 苏州华道生物药业股份有限公司 一种盐酸四咪唑的合成方法
CN115925559B (zh) * 2022-11-11 2024-12-17 上海泰坦科技股份有限公司 一种1-氨基-1-环戊基甲醇的制备方法

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WO2000042031A2 (en) 2000-07-20
WO2000042031A3 (en) 2000-11-09
CA2359562A1 (en) 2000-07-20
SV2002000005A (es) 2002-07-16
TR200102041T2 (tr) 2001-12-21
CN1337955A (zh) 2002-02-27
HUP0105134A2 (hu) 2002-04-29
CO5160338A1 (es) 2002-05-30
NO20013318D0 (no) 2001-07-04
IL144031A0 (en) 2002-04-21
KR20010089831A (ko) 2001-10-08
ZA200105253B (en) 2002-09-05
NO20013318L (no) 2001-08-30
AU2708700A (en) 2000-08-01
AR022214A1 (es) 2002-09-04
BR9916999A (pt) 2001-10-30
SK10032001A3 (sk) 2002-05-09
ID30514A (id) 2001-12-13
BG105761A (en) 2002-03-29
JP2002534517A (ja) 2002-10-15
CZ20012530A3 (cs) 2002-02-13
GT200000003A (es) 2001-07-06

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