US20030229058A1 - Aryl aniline beta2 adrenergic receptor agonists - Google Patents

Aryl aniline beta2 adrenergic receptor agonists Download PDF

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Publication number
US20030229058A1
US20030229058A1 US10/431,762 US43176203A US2003229058A1 US 20030229058 A1 US20030229058 A1 US 20030229058A1 US 43176203 A US43176203 A US 43176203A US 2003229058 A1 US2003229058 A1 US 2003229058A1
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United States
Prior art keywords
hydroxy
compound
alkyl
ethyl
aminophenyl
Prior art date
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Abandoned
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US10/431,762
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English (en)
Inventor
Edmund Moran
John Jacobsen
Michael Leadbetter
Matthew Nodwell
Sean Trapp
James Aggen
Timothy Church
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Theravance Biopharma R&D IP LLC
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Individual
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Priority claimed from US10/292,835 external-priority patent/US6670376B1/en
Priority to US10/431,762 priority Critical patent/US20030229058A1/en
Application filed by Individual filed Critical Individual
Assigned to THERAVANCE, INC. reassignment THERAVANCE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEADBETTER, MICHAEL R., MORAN, EDMUND J., TRAPP, SEAN G., AGGEN, JAMES B., CHURCH, TIMOTHY J, JACOBSEN, JOHN R., NODWELL, MATTHEW B.
Publication of US20030229058A1 publication Critical patent/US20030229058A1/en
Priority to AT04809361T priority patent/ATE447408T1/de
Priority to DE602004023946T priority patent/DE602004023946D1/de
Priority to PCT/US2004/014168 priority patent/WO2005025555A2/en
Priority to EP04809361A priority patent/EP1641465B1/en
Priority to JP2006514309A priority patent/JP2006525372A/ja
Priority to US11/805,101 priority patent/US7582765B2/en
Assigned to THERAVANCE BIOPHARMA R&D IP, LLC reassignment THERAVANCE BIOPHARMA R&D IP, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THERAVANCE, INC.
Abandoned legal-status Critical Current

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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
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    • 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
    • C07D277/44—Acylated amino or imino radicals
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the invention is directed to novel ⁇ 2 adrenergic receptor agonists.
  • the invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with ⁇ 2 adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.
  • ⁇ 2 adrenergic receptor agonists are recognized as effective drugs for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema). ⁇ 2 adrenergic receptor agonists are also useful for treating pre-term labor, and are potentially useful for treating neurological disorders and cardiac disorders.
  • pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema).
  • ⁇ 2 adrenergic receptor agonists are also useful for treating pre-term labor, and are potentially useful for treating neurological disorders and cardiac disorders.
  • current agents possess less than desirable potency, selectivity, speed of onset, and/or duration of action.
  • ⁇ 2 adrenergic receptor agonists having improved properties.
  • Preferred agents may possess, among other properties, improved duration of action, potency, selectivity, and/or onset.
  • the invention provides novel compounds that possess ⁇ 2 adrenergic receptor agonist activity. Accordingly, this invention provides compounds of formula (I):
  • each of R 1 -R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R a ;
  • R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 are joined together to form a group selected from the group consisting of —C(R d ) ⁇ C(R d )C( ⁇ O)NR d —, —CR d R d —CR d R d —C( ⁇ O)NR d —, —NR d C( ⁇ O)C(R d ) ⁇ C(R d )—, —NR d C( ⁇ O)CR d R d —CR d R d —, —NR d C( ⁇ O)S—, —SC( ⁇ O)NR d —, —(CR d R d ) p —, —S(CR d R d ) q —, —(CR d R d ) q S—, —S(CR d R d ) r O—, —O(CR
  • R 6 is hydrogen, alkyl, or alkoxy
  • R 7 is hydrogen or alkyl
  • R 8 is hydrogen or alkyl; or R 8 together with R 9 is —CH 2 — or —CH 2 CH 2 —;
  • R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R a , or R 9 together with R 8 is —CH 2 — or —CH 2 CH 2 —;
  • R 10 is hydrogen or alkyl
  • each R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —C( ⁇ O)R d , —CO 2 R d , —OC( ⁇ O)R d , —CN, —C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OC( ⁇ O)NR d R e , —NR d C( ⁇ O)OR e , —NR d C( ⁇ O)NR d R e , —OR d , S(O) m R d , —NR d —NR d —C( ⁇ O)R d , —NR d —N ⁇ CR d R d ,
  • R 11 and R 12 together with the atoms to which they are attached form a fused benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 R c ;
  • each alkyl, alkenyl, and alkynyl is optionally substituted with R m , or with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from R b ;
  • R 1 -R 6 , R 9 , and R 11 -R 13 each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R c , and for R 1 -R 6 , R 9 , and R 11 -R 13 each cycloalkyl and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b and R c ;
  • each R a is independently —OR d , —NO 2 , halo, —S(O) m R d , —S(O) 2 OR d , S(O) m NR d R e , —NR d R e , O(CR f R g ) n NR d R e , —C( ⁇ O)R d , —CO 2 R d , —CO 2 (CR f R g ) n CONR d R e , —OC( ⁇ O)R d , —CN, —C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OC( ⁇ O)NR d R e , —NR d C( ⁇ O)OR e , —NR d C( ⁇ O)NR d R e , —CR d ( ⁇ N—OR e ), —CF 3
  • each R b is independently R a , oxo, or ⁇ N—OR e ;
  • each R c is independently R a , alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b ;
  • each R d and R e is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from R h ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • each R f and R g is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R h ; or R f and R g together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • each R h is independently halo, C 1-8 alkyl, C 1-8 alkoxy, —S—C 1-8 alkyl, aryl, (aryl)-C 1-6 alkyl, (aryl)-C 1-8 alkoxy, heteroaryl, (heteroaryl)-C 1-6 alkyl, (heteroaryl)-C 1-8 alkoxy, hydroxy, amino, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —OC( ⁇ O)C 1-6 alkyl, —C( ⁇ O)C 1-6 alkyl, —C( ⁇ O)OC 1-6 alkyl, —NHC( ⁇ O)C 1-6 alkyl, —C( ⁇ O)NHC 1-6 alkyl, carboxy, nitro, —CN, or —CF 3 ;
  • R j and R k together with the carbon atoms to which they are attached form a phenyl ring that is optionally substituted with 1, 2, 3, or 4 R c ;
  • each R m is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of R c , and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents selected from R b ;
  • m is 0, 1, or 2;
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • p is 3, 4, or 5;
  • q is 2, 3, or 4;
  • r is 1,2, or 3;
  • w is 0, 1, 2, 3, or 4;
  • the invention also provides compounds of formula (IIa):
  • R 4 is —CH 2 OH or —NHCHO and R 5 is hydrogen; or R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH—;
  • R 11 is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, —OR d , —CN, —NO 2 , —SO 2 R d , —C( ⁇ O)R d , C( ⁇ O)NR d R e , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each R d and R e is independently hydrogen or C 1-3 alkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 C 1-3 alkyl substituents; and
  • R 12 is hydrogen or —OC 1-6 alkyl
  • the invention also provides compounds of formula (IIb):
  • R 4 is —CH 2 OH or —NHCHO and R 5 is hydrogen; or R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH—;
  • R 12 is hydrogen or —OC 1-6 alkyl
  • R 17 is —(CH 2 ) x NR d R e wherein each R d and R e is independently hydrogen or C 1-4 alkyl, wherein each C 1-4 alkyl is optionally substituted with phenyl or pyridyl, or R d and R e together with the nitrogen atom to which they are attached is morpholino; and
  • x is 0, 1, or 2.
  • the invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier.
  • the invention further provides combinations comprising a compound of the invention and one or more other therapeutic agents and pharmaceutical compositions comprising such combinations.
  • the invention also provides a method of treating a disease or condition associated with ⁇ 2 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • a disease or condition associated with ⁇ 2 adrenergic receptor activity e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation
  • the invention further provides a method of treatment comprising administering a therapeutically effective amount of a combination of a compound of the invention together with one or more other therapeutic agents.
  • the invention also provides a method of treating a disease or condition associated with ⁇ 2 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition of the invention.
  • a disease or condition associated with ⁇ 2 adrenergic receptor activity e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation
  • This invention also provides a method of modulating a ⁇ 2 adrenergic receptor, the method comprising stimulating a ⁇ 2 adrenergic receptor with a modulatory amount of a compound of the invention.
  • the invention also provides synthetic processes and novel intermediates, including compounds of formulas (III), (IV), and (VII) described herein, which are useful for preparing compounds of the invention.
  • the invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition associated with ⁇ 2 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal.
  • a disease or condition associated with ⁇ 2 adrenergic receptor activity e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation
  • alkyl refers to a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Such alkyl groups preferably contain from 1 to 20 carbon atoms; more preferably, from 1 to 8 carbon atoms; and still more preferably, from 1 to 4 carbon atoms.
  • Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkenyl refers to a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond, typically 1 or 2 carbon-carbon double bonds, and which may be linear or branched or combinations thereof. Such alkenyl groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; and still more preferably, from 2 to 4 carbon atoms.
  • alkenyl groups include, by way of example, vinyl, allyl, isopropenyl, but-2-enyl, n-pent-2-enyl, n-hex-2-enyl, n-hept-2-enyl, n-oct-2-enyl, n-non-2-enyl, n-dec-4-enyl, n-dec-2,4-dienyl and the like.
  • alkynyl refers to a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, typically 1 carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Such alkynyl groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; and still more preferably, from 2 to 4 carbon atoms. Representative alkynyl groups include, by way of example, ethynyl, propargyl, but-2-ynyl and the like.
  • alkoxy refers to a group of the formula —OR, where R is an alkyl group as defined herein.
  • Representative alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.
  • cycloalkyl refers to a monovalent saturated carbocyclic group which may be monocyclic or multicyclic. Each ring of such cycloalkyl groups preferably contains from 3 to 10 carbon atoms. This term also includes cycloalkyl groups fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic (cycloalkyl) portion of the group.
  • Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2,3,4-tetrahydronaphth-2-yl, decahydronaphthyl, indan-1-yl, adamantyl, norbornyl and the like.
  • aryl refers to a monovalent carbocyclic group which may be monocyclic or multicyclic (i.e., fused) wherein at least one ring is aromatic. Such aryl groups preferably contain from 6 to 20 carbon atoms; more preferably, from 6 to 10 carbon atoms. This term includes multicyclic carbocyclic ring systems wherein one or more rings are not aromatic, provided the point of attachment is on an aromatic ring. Representative aryl groups include, by way of example, phenyl, napthyl, azulenyl, indan-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, and the like.
  • heteroaryl refers to a monovalent aromatic group that contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from N, S and O, and which may be monocyclic or multicyclic (i.e., fused). Such heteroaryl groups preferably contain from 5 to 20 atoms; more preferably, from 5 to 10 atoms. This term also includes heteroaryl groups fused to a cycloalkyl or aryl group, in which the point of attachment is on the aromatic (heteroaryl) portion of the group.
  • heteroaryl groups include, by way of example, pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl (or, equivalently, pyridinyl), oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl and the like.
  • heterocyclyl or “heterocyclic ring” refers to a saturated or partially unsaturated cyclic non-aromatic group, which may be monocyclic or multicyclic (i.e., fused or bridged), and which contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from N(X), S and O, wherein each X is independently hydrogen or alkyl.
  • heterocyclyl groups preferably contain from 3 to 20 atoms; more preferably, from 3 to 10 atoms. This term also includes such a heterocyclyl group fused to one or more cycloalkyl, aryl, or heteroaryl groups.
  • heterocyclyl group may be any carbon or nitrogen atom in a heterocyclyl, cycloalkyl, aryl or heteroaryl portion of the group.
  • Representative heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl, 2-oxobenzopyran, and the like.
  • halo refers to a fluoro, chloro, bromo or iodo.
  • oxo refers to a group of the formula ⁇ O.
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), and includes:
  • disease or condition associated with ⁇ 2 adrenergic receptor activity includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with ⁇ 2 adrenergic receptor activity.
  • disease states include, but are not limited to, bronchoconstrictive or pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as neurological disorders and cardiac disorders.
  • ⁇ 2 Adrenergic receptor activity is also known to be associated with pre-term labor (see, for example, U.S. Pat. No. 5,872,126) and some types of inflammation (see, for example, WO 99/30703 and U.S. Pat. No. 5,290,815).
  • salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1-hydroxy-2-naphthoic acid) and the like.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • arginine betaine
  • caffeine choline
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, i.e. a compound of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent.
  • solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.
  • Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
  • leaving group refers to a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • amino-protecting group refers to a protecting group suitable for preventing undesired reactions at an amino nitrogen.
  • Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
  • hydroxy-protecting group refers to a protecting group suitable for preventing undesired reactions at a hydroxy group.
  • Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups for example alkanoyl groups, such as acetyl
  • arylmethyl groups such as benzyl (Bn), p-
  • R 1 A specific value for R 1 is hydrogen.
  • a specific value for R 2 is hydrogen.
  • a specific value for R 3 is hydroxy.
  • R 4 is —CH 2 OH or —NHCHO.
  • a specific value for R 5 is hydrogen.
  • R 4 and R 5 together are —NHC( ⁇ O)CH ⁇ CH— or —SC( ⁇ O)NH—.
  • a specific value for R 6 is hydrogen.
  • a specific value for R 7 is hydrogen.
  • a specific value for R 8 is hydrogen.
  • a specific value for w is 0.
  • w is 1 or 2.
  • R 9 together with R 8 is —CH 2 — or —CH 2 CH 2 —.
  • R 10 A specific value for R 10 is hydrogen.
  • R 10 Another specific value for R 10 is alkyl.
  • R 11 is hydrogen
  • R 11 Another specific value for R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —C( ⁇ O)R d , —CO 2 R d , —OC( ⁇ O)R d , —CN, —C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OC( ⁇ O)NR d R e , —NR d C( ⁇ O)OR e , —NR d C( ⁇ O)NR d R e , —OR d , —S(O) m R d , —NR d —NR d —C( ⁇ O)R d , —NR d —N ⁇ CR d R d , —N(NR d R e )R d , or —S(O
  • R 11 is hydrogen, alkyl, heterocyclyl, —OR d , —S(O) m R d , or —S(O) 2 NR d R e .
  • R 11 Another specific value for R 11 is heterocyclyl, —OR d , —S(O) m R d , or —S(O) 2 NR d R e .
  • R 11 Another specific value for R 11 is —OR d .
  • R 11 Another specific value for R 11 is —S(O) m R d .
  • a specific value for R 12 is hydrogen.
  • R 12 Another specific value for R 12 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —C( ⁇ O)R d , —CO 2 R d , —OC( ⁇ O)R d , —CN, —C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OC( ⁇ O)NR d R e , —NR d C( ⁇ O)OR e , —NR d C( ⁇ O)NR d R e , —OR d , —S(O) m R d , —NR d —NR d —C( ⁇ O)R d , —NR d —N ⁇ CR d R d , —N(NR d R e )R d , or S(O)
  • R 12 Another specific value for R 12 is hydrogen, alkyl, heterocyclyl, —OR d , —S(O) m R d , or —S(O) 2 NR d R e .
  • R 12 is heterocyclyl, —OR d , —S(O) m R d , or —S(O) 2 NR d R e .
  • R 12 Another specific value for R 12 is —OR d .
  • R 12 Another specific value for R 12 is —S(O) m R d .
  • R 12 Another specific value for R 12 is —S(O) 2 NR d R e .
  • a specific value for R 13 is hydrogen.
  • R 13 Another specific value for R 13 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —C( ⁇ O)R d , —CO 2 R d , —OC( ⁇ O)R d , —CN, C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OC( ⁇ O)NR d R e , —NR d C( ⁇ O)OR e , —NR d C( ⁇ O)NR d R e , —OR d , —S(O) m R d , —NR d —NR d —C( ⁇ O)R d , —NR d —N ⁇ CR d R d , —N(NR d R e )R d , or S(O) 2
  • R 13 Another specific value for R 13 is hydrogen, alkyl, heterocyclyl, —OR d , S(O) m R d , or —S(O) 2 NR d R e .
  • R 13 Another specific value for R 13 is heterocyclyl, —OR d , —S(O) m R d , or —S(O) 2 NR d R e .
  • a specific value for R 13 is —OR d .
  • R 11 A specific value for R 11 is —S(O) m R d .
  • a specific group of compounds of the invention are compounds wherein each of R 1 -R 4 is independently selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxy, N,N-dimethylaminocarbonyloxy, —CH 2 OH, and —NHCHO, and R 5 is hydrogen; or R 1 is hydrogen, R 2 is hydrogen, R 3 is hydroxy, and R 4 and R 5 together are —NHC( ⁇ O)CH ⁇ CH— or —SC( ⁇ O)NH—.
  • a specific group of compounds of the invention are compounds wherein R 1 is hydrogen; R 2 is chloro; R 3 is amino; R 4 is chloro; and R 5 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 1 is hydrogen; R 2 is N,N-dimethylaminocarbonyloxy; R 3 is hydrogen; R 4 is N,N-dimethylaminocarbonyloxy; and R 5 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 1 is hydrogen, fluoro, or chloro; R 2 is hydroxy; R 3 is hydrogen; R 4 is hydroxy; and R 5 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 1 is chloro; R 2 is hydrogen; R 3 is hydroxy; R 4 is hydrogen; and R 5 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R is hydrogen; R 2 is hydrogen; R 3 is hydroxy; R 4 is —CH 2 OH; and R 5 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 1 is hydrogen; R 2 is hydrogen; R 3 is hydroxy; R 4 is —NHCHO; and R 5 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 1 is hydrogen; R 2 is hydrogen; R 3 is hydroxy; and R 4 and R 5 together are —NHC( ⁇ O)CH ⁇ CH—.
  • a specific group of compounds of the invention are compounds wherein R 1 is hydrogen; R 2 is hydrogen; R 3 is hydroxy; and R 4 and R 5 together are —SC( ⁇ O)NH—.
  • a specific group of compounds of the invention are compounds wherein R 11 is hydrogen, R 12 is —SR d ; R 13 is hydrogen; and R d is alkyl, aryl, or heteroaryl.
  • a specific group of compounds of the invention are compounds wherein R 11 is —SR d , R 12 is hydrogen; R 13 is hydrogen; and R d is alkyl, aryl, heteroaryl.
  • R d When part of the group —SR d , a specific value for R d is alkyl.
  • R d When part of the group —SR d , another specific value for R d is C 1-6 alkyl.
  • Rd is C 1-3 alkyl.
  • R d is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, —N(C 1-6 alkyl) 2 , nitro, —CN, and —CF 3 .
  • R d When part of the group —SR d , another more specific value for R d is phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from fluoro and C 1-3 alkyl.
  • a specific group of compounds of the invention are compounds wherein R 11 or R 12 is methylthio, 2-methylphenylthio, 4-methyl-2-pyrimidylthio, 4-fluorophenylthio, or 4-methylphenylthio.
  • a specific group of compounds of the invention are compounds wherein R 11 is hydrogen or alkyl, R 12 is —SO 2 NR d R e ; and R 11 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 11 is —SO 2 NR d R e , R 12 is hydrogen or alkyl; and R 11 is hydrogen.
  • R d is alkyl, aryl, or heteroaryl
  • R e is hydrogen, alkyl, aryl, or heteroaryl
  • each alkyl, aryl, or heteroaryl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from R h ; or R d and R e together with the nitrogen atom to which they are attached is a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen.
  • R d and R e independently is hydrogen, alkyl, aryl, or heteroaryl; wherein each alkyl, aryl, or heteroaryl, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R h .
  • R h is halo, C 1-8 alkyl, C 1-8 alkoxy, —S—C 1-8 alkyl, aryl, hydroxy, amino, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —OC( ⁇ O)C 1-6 alkyl, —C( ⁇ O)C 1-6 alkyl, —C( ⁇ O)OC 1-6 alkyl, —NHC( ⁇ O)C 1-6 alkyl, —C( ⁇ O)NHC 1-6 alkyl, carboxy, nitro, —CN, or —CF 3 .
  • R h Another specific value for R h in the above context is halo, C 1-6 alkyl, C 1-6 alkoxy, or —CF 3 .
  • a specific value for R d and R e together with the nitrogen atom to which they are attached is a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen.
  • R d and R e independently is alkyl; wherein each alkyl is optionally substituted with 1 or 2 alkoxy substituents.
  • R d or R e When part of the group —SO 2 NR d R e , a specific value for R d or R e is phenyl, or naphthyl; wherein each phenyl and naphthyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, and —CF 3 .
  • a specific value for R d or R e is heteroaryl; wherein each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, and —CF 3 .
  • heteroaryl is pyridyl, pyrimidyl, or thiazolyl.
  • a preferred group of compounds are compounds wherein R 11 or R 12 is —SO 2 NR d R e ; wherein R d is 4-heptyl-6-methyl-2-pyrimidyl, 5-methoxy-2-pyrimidyl, 2-pyridyl, phenyl, 2,6-dimethylphenyl, 2-thiazoyl, 2-trifluoromethylphenyl, or 3,5-dichlorophenyl; and R e is hydrogen or ethyl.
  • R 11 or R 12 is —SO 2 NR d R e ; wherein R d and R e together with the atoms to which they are attached are piperidino or morpholino.
  • a specific group of compounds of the invention are compounds wherein R 11 is hydrogen or alkyl; R 12 is —SO 2 R d ; and R 13 is hydrogen.
  • R 11 is —SO 2 R d ;
  • R 12 is hydrogen or alkyl; and
  • R 13 is hydrogen.
  • R d When part of the group —SO 2 R d , a specific value for R d is alkyl, aryl, or heteroaryl.
  • R d When part of the group —SO 2 R d , a specific value for R d is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, and —CF 3 .
  • R d When part of the group —SO 2 R d , a specific value for R d is phenyl optionally substituted with 1 or 2 substituents independently selected from halo and C 1-6 alkyl.
  • a preferred group of compounds of the invention are compounds wherein R 11 or R 12 is —SO 2 R d ; wherein R d is phenyl, 4-chlorophenyl, methyl, or 4-fluorophenyl.
  • a specific group of compounds of the invention are compounds wherein at least one of R 11 , R 12 , and R 13 is —OR d and each of the other two of R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halo; wherein any alkyl or —O-alkyl is optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo substituents.
  • a specific group of compounds of the invention are compounds wherein R 11 is —OR d .
  • a specific group of compounds of the invention are compounds wherein R 12 is —OR d
  • a specific group of compounds of the invention are compounds wherein R 13 is —OR d
  • a specific group of compounds of the invention are compounds wherein R 11 is hydrogen; R 12 is —OR d ; and R 13 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 11 is —OR d ; R 12 is hydrogen; and R 13 is hydrogen.
  • R d When part of the group —OR d , a specific value for R d is alkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo substituents and also optionally substituted with 1, 2, 3, or 4 aryl substituents, wherein each aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —OC( ⁇ O)C 1-6 alkyl, —C( ⁇ O)C 1-6 alkyl, —C( ⁇ O)OC 1-6 alkyl, —NHC( ⁇ O)C 1-6 alkyl, —C( ⁇ O)NHC 1-6 alkyl, carboxy, nitro, —CN, and —CF 3 .
  • substituents independently selected from halo, C 1-6 alkyl, C 1-6 al
  • R d When part of the group —OR d , a specific value for R d is alkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo substituents and also optionally substituted with 1 or 2 phenyl substituents, wherein each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, —CN, and —CF 3 .
  • a specific group of compounds of the invention are compounds wherein R 11 and R 12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered ring comprising one or more carbon atoms and 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen; and R 13 is selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halo; wherein any alkyl or —O-alkyl is optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo substituents.
  • a more specific group of compounds of the invention are compounds wherein R 11 and R 12 together are —OCH 2 O—, —OCH 2 CH 2 O—, or —OCH 2 CH 2 CH 2 O—.
  • a specific group of compounds of the invention are compounds wherein R 11 , R 12 or R 13 is methoxy, ethoxy, benzyloxy, or isopropoxy.
  • a specific group of compounds of the invention are compounds wherein R 11 , R 12 and R 13 are each hydrogen.
  • a specific group of compounds of the invention are compounds wherein at least one of R 11 , R 12 , and R 13 is alkyl and each of the other two of R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents; or wherein R 11 and R 12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring.
  • a specific group of compounds of the invention are compounds wherein at least one of R 11 , R 12 , and R 13 is alkyl and each of the other two of R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
  • a specific group of compounds of the invention are compounds wherein R 11 and R 12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring; and R 13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
  • a specific value for R 13 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 11 is hydrogen; R 12 is alkyl; and R 13 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 11 is alkyl; R 12 is hydrogen; and R 13 is hydrogen.
  • a preferred group of compounds of the invention are compounds wherein R 11 or R 12 is methyl, ethyl, isopropyl, or cyclohexyl; or wherein R 11 and R 12 taken together are —CH 2 CH 2 CH 2 —.
  • a specific group of compounds of the invention are compounds wherein at least one of R 11 , R 12 , and R 13 is aryl; and each of the other two of R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halo, wherein any alkyl or —O-alkyl is optionally substituted with aryl, with one or more (e.g. l, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents;
  • a specific group of compounds of the invention are compounds wherein at least one of R 11 , R 12 , and R 13 is aryl; and each of the other two of R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halo, wherein any alkyl or —O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
  • a specific group of compounds of the invention are compounds wherein R 11 is phenyl, optionally substituted with 1, 2, 3, or 4 alkyl, —OR d , —NO 2 , halo, —NR d R e , —C( ⁇ O)R d , —CO 2 R d , —OC( ⁇ O)R d , —CN, —C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OC( ⁇ O)NR d R e , —NR d C( ⁇ O)OR e , —NR d C( ⁇ O)NR d R e , —CR d ( ⁇ N—OR e ), —CF 3 , or —OCF 3 ;
  • R 12 is selected from the group consisting of hydrogen and —O-alkyl, optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo
  • a specific group of compounds of the invention are compounds wherein R 11 is phenyl, optionally substituted with 1, 2, 3, or 4 alkyl, —OR d , halo, —CF 3 , or —OCF 3 ; R 12 is selected from the group consisting of hydrogen and —O-alkyl, optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo; and R 13 is hydrogen.
  • a specific group of compounds of the invention are compounds wherein R 11 or R 12 is phenyl.
  • a specific group of compounds of the invention are compounds wherein R 11 and R 12 together with the atoms to which they are attached form a fused benzo ring.
  • a specific group of compounds of the invention are compounds wherein at least one of R 11 , R 12 , and R 13 is heterocyclyl; and each of the other two of R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halo, wherein any alkyl or —O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents;
  • a specific group of compounds of the invention are compounds wherein R 11 and R 12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered ring comprising carbon atoms and optionally comprising 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen, wherein said ring can optionally be substituted on carbon with one or two oxo ( ⁇ O), and wherein said ring is fused to a benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 R e ; and R 13 is independently selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halo, wherein any alkyl or —O-alkyl is optionally substituted with aryl, with one or more halo, or with 1 or 2-O-alkyl substituents.
  • a specific group of compounds of the invention are compounds wherein R 11 or R 12 is 2,3-dihydro-5-methyl-3-oxo-1-pyrazolyl; or wherein R 11 and R 12 together with the atoms to which they are attached form a 2-oxobenzopyran ring.
  • R 11 or R 12 is anilino, trifluoromethoxy, or methoxycarbonyl.
  • a sub-group of compounds of the invention are compounds of formula (I) wherein each of R 1 -R 5 is independently selected from the group consisting of hydrogen, alkyl, and R a ; wherein each R a is independently —OR d , halo, —NR d R e , —NR d C( ⁇ O)R e , or —OC( ⁇ O)NR d R e ;
  • R 6 , R 8 , and R 10 are each hydrogen;
  • each of R 11 and R 12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —CO 2 R d , —OC( ⁇ O)R d , —CN, —C( ⁇ O)NR d R e , —NR d C( ⁇ O)R e , —OR d , S(O) m R d , —NR d —NR d —C( ⁇ O)R d , —NR d —N ⁇ CR d R d , —N(NR d R e )R d , and —S(O) 2 NR d R e ;
  • each alkyl is optionally substituted with R m , or with 1, 2, 3, or 4 substituents independently selected from R b ;
  • each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R c , and for R 11 and R 12 , each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b and R c ;
  • R 13 is hydrogen
  • the group comprising —NR 10 is meta or para to the group comprising R 7 ;
  • w is 0, 1, or 2.
  • each of R 11 and R 12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, —OR d , —S(O) m R d , and —S(O) 2 NR d R e ; wherein each alkyl is optionally substituted with 1 or 2 substituents independently selected from R b , each aryl is optionally substituted with 1 or 2 substituents independently selected from R c , and each heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from R b and R c ; and m is 0 or 2.
  • R 7 is hydrogen
  • each of R 11 and R 12 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, cyclohexyl, phenyl, pyrazolinyl, —OR d , —S(O) m R d , and —S(O) 2 NR d R e ;
  • R d and R e are independently selected from the group consisting of hydrogen, C 1-6 alkyl, phenyl, —CF 3 , and C 1-3 alkyl, pyridyl, thiazolyl, pyrimidinyl, and pyrazolinyl, where each phenyl is optionally substituted with 1 or 2 substitutents independently selected from halo, —CF 3 , and C 1-3 alkyl, each pyrimidinyl is optionally substituted with 1 or 2 substitutents independently selected from C 1-3 alkyl and OC 1-3 alkyl, and each pyrazolinyl is optionally substituted with 1 or 2 substitutents independently selected from C 1-3 alkyl and carboxy; or
  • R d and R e together with the nitrogen atom to which they are attached are morpholino or piperidino.
  • one most preferred sub-group of compounds are compounds wherein R 11 is —SR d and R 12 is hydrogen, or R 11 is hydrogen and R 12 is —SR d , wherein R d is selected from the group consisting of C 1-3 alkyl, phenyl, and pyrimidinyl, and wherein each phenyl is optionally substituted with 1 or 2 substitutents independently selected from halo and C 1-3 alkyl, and each pyrimidinyl is optionally substituted with C 1-3 alkyl.
  • R 11 is —S(O) 2 NR d R e and R 12 is hydrogen or alkyl
  • R 11 is hydrogen or alkyl
  • R 12 is —S(O) 2 NR d R e
  • R d and R e are independently selected from the group consisting of hydrogen, C 1-3 alkyl, phenyl, pyridyl, thiazolyl, and pyrimidinyl, and wherein each phenyl is optionally substituted with 1 substitutent selected from halo and C 1-3 alkyl, and each pyrimidinyl is optionally substituted with 1 substitutent selected from C 1-3 alkyl and O—C 1-3 alkyl; or R d and R e , together with the nitrogen atom to which they are attached are morpholino or piperidino.
  • R 11 is —SO 2 R d and R 12 is hydrogen, or R 11 is hydrogen and R 12 is —SO 2 R d , wherein Rd is C 1-3 alkyl or phenyl, and wherein each phenyl is optionally substituted with 1 substituent selected from halo and C 1-3 alkyl.
  • R 11 is —OR d and R 12 is hydrogen or —OR d ; or R 11 is hydrogen and R 12 is —OR d , wherein R d is C 1-3 alkyl.
  • R 11 is C 1-3 alkyl and R 12 is hydrogen or C 1-3 alkyl; or R 11 is cyclohexane and R 12 is hydroxy.
  • R 11 is hydrogen or phenyl; and R 12 is —OC 1-3 alkyl; or wherein R 11 is phenyl and R 12 is hydrogen.
  • Yet another most preferred sub-group of compounds within the more preferred sub-group defined above are compounds wherein R 12 is hydrogen and R 11 is SO 2 NR d R e , wherein R d and R e , together with the nitrogen atom to which they are attached, are morpholino or piperidino.
  • R 4 is —CH 2 OH or —NHCHO and R 5 is hydrogen; or R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH—;
  • R 11 is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, —OR d , —CN, —NO 2 , —SO 2 R d , —C( ⁇ O)R d , —C( ⁇ O)NR d R e , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each R d and R e is independently hydrogen or C 1-3 alkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 C 1-3 alkyl substituents; and
  • R 12 is hydrogen or —OC 1-6 alkyl.
  • R 11 is phenyl, optionally substituted with 1 or 2 substituents selected from halo, —OR d , —CN, —NO 2 , SO 2 R d , —C( ⁇ O)R d , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and R d is hydrogen or C 1-3 alkyl; or R 11 is pyridyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, or indolyl, each of which is optionally substituted with 1 or 2 C 1-3 alkyl substituents.
  • R 11 is phenyl, pyridyl, or thiophenyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, —OCH 3 , —CN, and —CH 2 NH 2 ; and R 12 is hydrogen, —OCH 3 , or —OC 2 H 5 .
  • R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH—
  • R 11 is phenyl or pyridyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, —OCH 3 , —CN, and —CH 2 NH 2
  • R 12 is —OCH 3 .
  • R is —CH 2 OH or —NHCHO and R 5 is hydrogen; or R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH—;
  • R 12 is hydrogen or —OC 1-6 alkyl
  • R 17 is —(CH 2 ) x NR d R e wherein each R d and R e is independently hydrogen or C 1-4 alkyl, wherein each C 1-4 alkyl is optionally substituted with phenyl or pyridyl, or R d and R e together with the nitrogen atom to which they are attached is morpholino; and
  • x is 0, 1, or 2.
  • R 12 is hydrogen, —OCH 3 , or —OC 2 H 5 ; and R 17 is —CH 2 NR d R e wherein each R d and R e is independently hydrogen or C 1-4 alkyl, or R d is hydrogen and Re is C 1-4 alkyl substituted with phenyl or pyridyl, or R d and R e together with the nitrogen atom to which they are attached is morpholino.
  • Particularly preferred are compounds of formula (IIb) wherein R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH— and R 12 and R 17 are as defined immediately above.
  • a preferred compound is any one of compounds 1-117 shown in the Examples below.
  • Most preferred compounds of the invention include the following:
  • the invention also includes pharmaceutically-acceptable salts of the compounds of the invention.
  • a preferred pharmaceutically-acceptable salt of compound 61 is the hydrochloride salt.
  • the compounds of the invention contain one or more chiral centers Accordingly, the invention includes racemic mixtures, pure stereoisomers (i.e. individual enantiomers or diastereomers), and stereoisomer-enriched mixtures of such isomers, unless otherwise indicated.
  • stereoisomer is shown, it will be understood by those skilled in the art, that minor amounts of other stereoisomers may be present in the compositions of this invention unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers.
  • compounds of the invention contain a chiral center at the alkylene carbon in formulas (I) and (II) to which the hydroxy group is attached.
  • the amount of the stereoisomer with the (R) orientation at the chiral center bearing the hydroxy group is advantageous for the amount of the stereoisomer with the (R) orientation at the chiral center bearing the hydroxy group to be greater than the amount of the corresponding (S) stereoisomer.
  • the (R) stereoisomer is preferred over the (S) stereoisomer.
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be used to prevent certain functional groups from undergoing undesired reactions.
  • Representative examples of amino-protecting groups and hydroxy-protecting groups are given above. Typical procedures for their removal include the following.
  • An acyl amino-protecting group or hydroxy-protecting group may conveniently be removed, for example, by treatment with an acid, such as trifluoroacetic acid.
  • An arylmethyl group may conveniently be removed by hydrogenolysis over a suitable metal catalyst such as palladium on carbon.
  • a silyl hydroxy-protecting group may conveniently be removed by treatment with a fluoride ion source, such as tetrabutylammonium fluoride, or by treatment with an acid, such as hydrochloric acid.
  • a compound of formula (I) can be prepared by deprotecting a corresponding compound of formula (III):
  • R 15 is an amino-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I), comprising deprotecting a corresponding compound of formula (III), wherein R 15 is an amino-protecting group (e.g. 1,1-(4-methoxyphenyl)methyl or benzyl).
  • R 15 is an amino-protecting group (e.g. 1,1-(4-methoxyphenyl)methyl or benzyl).
  • a compound of formula (I) wherein R 3 is hydroxy can be prepared by deprotecting a corresponding compound of formula (I) wherein R 3 is —OPg 1 and Pg 1 is a hydroxy-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I) wherein R 3 is hydroxy, comprising deprotecting a corresponding compound of formula (I) wherein R 3 is —OPg 1 and Pg 1 is a hydroxy-protecting group (e.g. benzyl).
  • a compound of formula (I) wherein R 3 is hydroxy can also be prepared by deprotecting a corresponding compound of formula (III) wherein R 5 is an amino-protecting group and wherein R 3 is —OPg 1 wherein Pg 1 is a hydroxy-protecting group.
  • the invention provides a method for preparing a compound of formula (I), comprising deprotecting a corresponding compound of formula (E) wherein R 15 is an amino-protecting group (e.g. benzyl) and R 3 is —OPg 1 wherein Pg 1 is a hydroxy-protecting group (e.g. benzyl).
  • the invention also provides an intermediate compound of formula (III) wherein R 15 is an amino-protecting group (e.g. 1,1-di-(4′-methoxyphenyl)methyl or benzyl); as well as an intermediate compound of formula (I) wherein R 3 is —OPg 1 and Pg 1 is a hydroxy-protecting group; and an intermediate compound of formula (III) wherein R 15 is an amino-protecting group (e.g. benzyl), R 3 is —OPg 1 , and Pg 1 is a hydroxy-protecting group (e.g. benzyl).
  • R 15 is an amino-protecting group
  • R 3 is —OPg 1
  • Pg 1 is a hydroxy-protecting group
  • An intermediate compound of formula (III) can be prepared by reacting an amine of formula (V) with a compound of formula (IV), wherein R 16 is hydrogen or a hydroxy-protecting group (e.g. tert-butyldimethylsilyl) and X is a suitable leaving group (e.g. bromo).
  • R 16 is hydrogen or a hydroxy-protecting group (e.g. tert-butyldimethylsilyl) and X is a suitable leaving group (e.g. bromo).
  • the invention provides a method for preparing a compound of formula (III), comprising reacting a corresponding aniline of formula (V) with a corresponding compound of formula (IV), wherein X is a suitable leaving group (e.g. bromo) and R 15 is an amino-protecting group, in the presence of a transition metal catalyst.
  • R is a hydroxy-protecting group
  • the intermediate formed by the reaction of a compound of formula (V) with a compound of formula (IV) is subsequently deprotected to form the intermediate of formula (III).
  • suitable conditions for this reaction as well as suitable leaving groups are illustrated in the Examples and are also known in the art.
  • a compound of formula (III) can also be prepared by reacting an amine of formula (VII):
  • R 14 is hydrogen and R 15 is an amino-protecting group (e.g. benzyl), with a compound of formula (VI), (VIII), or (IX):
  • R 16 is hydrogen or a hydroxy-protecting group (e.g. tert-butyldimethylsilyl) and Z is a leaving group.
  • the invention provides a method for preparing a compound of formula (III), comprising reacting a corresponding amine of formula (VII), wherein R 14 is hydrogen and R 15 is an amino-protecting group, with a corresponding compound of formula (VI), (VIII), or (IX), wherein R 16 is hydrogen or a hydroxy-protecting group and Z is a suitable leaving group (e.g. bromo).
  • R is a hydroxy-protecting group
  • the intermediate formed by the reaction of a compound of formula (VII) with a compound of formula (VI) is subsequently deprotected to form the intermediate of formula (III).
  • the invention also provides a method for preparing a compound of formula (I), wherein R 3 is —OPg 1 and Pg 1 is a hydroxy-protecting group, comprising reacting a corresponding compound of formula (VII) wherein R 14 and R 15 are each hydrogen with a corresponding compound of formula (VI), wherein R 3 is —OPg 1 and Pg 1 is a hydroxy-protecting group and R 16 is a hydroxy-protecting group.
  • a compound of formula (I) wherein R 3 is hydroxy and R 13 is hydrogen can be prepared by reacting an intermediate of formula (I) wherein R 3 is —OPg 1 , where Pg 1 is a hydroxy-protecting group, and R 11 is a suitable leaving group (e.g. bromo) with an appropriately substituted boronic acid to form an intermediate, which is subsequently deprotected, as illustrated in Examples 65-102.
  • a compound of formula (I) can be prepared by coupling an intermediate of formula (IV) wherein R 15 is hydrogen and R 16 is a hydroxy-protecting group with a compound of formula (V), where the remaining variables are defined as in formula (I), in the presence of a transition metal catalyst, typically palladium, to form a protected intermediate, followed by removing the protecting group R 16 to form a compound of formula (I).
  • a transition metal catalyst typically palladium
  • a palladium-based catalyst is typically used in the process of coupling intermediates (IV) and (V) to provide a diarylamine compound of formula (I).
  • intermediates (IV) and (V) to provide a diarylamine compound of formula (I).
  • the compounds of this invention or intermediates thereof can be contaminated with unacceptable levels of palladium impurities. It has now been discovered that such palladium impurities can be removed from compounds of this invention or intermediates thereof using a functionalized solid support comprising (1-thioureido)alkyl or (mercapto)alkyl groups.
  • the compound to be purified of palladium is dissolved in a solvent compatible with the solid support, where a compatible solvent is one that does not affect the performance of the functionalized solid support. If the compound is in a free base form, an amount of acid, preferably hydrochloric acid, sufficient to convert the basic nitrogens of the compound to protonated form is added. Between about 1.05 and about 1.2 equivalents of HCl per basic nitrogen is a sufficient amount.
  • the resulting solution is diluted further with solvent and a functionalized solid support comprising (1-thioureido)alkyl or (mercapto)alkyl groups is added.
  • the solid support is a silica gel comprising 3-(1-thioureido)propyl or 3-(mercapto)propyl groups.
  • a preferred solvent compatible with the functionalized silica gel is a mixture of dichloromethane and methanol.
  • this invention provides a method of reducing the amount of palladium in a composition comprising a diarylamine compound and palladium, the method comprising (a) contacting a solution comprising a diarylamine compound having one or more basic nitrogen atoms wherein each nitrogen atom has been protonated with an acid, palladium, and a solvent, with a functionalized solid support comprising (1-thioureido)alkyl or (mercapto)alkyl groups; and (b) separating the resulting solution from the solid support to provide a composition having a reduced amount of palladium, wherein the solvent is compatible with the functionalized solid support.
  • the invention provides a method of reducing palladium in a composition wherein the diarylamine compound is N- ⁇ 2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl ⁇ -(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine.
  • the acid is hydrochloric acid;
  • the solvent comprises a mixture of dichloromethane and methanol, and the functionalized solid support is a silica gel comprising 3-(1-thioureido)propyl or 3-(mercapto)propyl groups.
  • the invention further provides a compound produced by the process comprising (a) coupling an intermediate of formula (IV) wherein R 15 is hydrogen and R 16 is a hydroxy-protecting group with a compound of formula (V), where the remaining variables are defined as in formula (I) and R 3 can additionally be defined as —OPg 1 , in the presence of a palladium catalyst, to form a protected intermediate; (b) removing the protecting group R 16 from the protected intermediate to form a compound of formula (I); (c) contacting a solution comprising the compound of formula (I), wherein each nitrogen atom has been protonated with an acid, and a solvent, with a functionalized solid support comprising (1-thioureido)alkyl or 3-(mercapto)alkyl groups, wherein the solvent is compatible with the functionalized solid support; (d) separating the resulting solution from the functionalized solid support; and, when R 3 is —OPg 1 , (d) removing the protecting group to form a compound in which R 3 is
  • the invention provides a compound produced by the process immediately above wherein R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 13 are each hydrogen, R 3 is —OPg 1 wherein Pg 1 is benzyl, R 4 and R 5 taken together are —NHC( ⁇ O)CH ⁇ CH—, R 11 is phenyl, R 12 is —OCH 3 , the leaving group X in formula (IV) is attached at the para position; the acid is hydrochloric acid; the solvent is a mixture of dichloromethane and methanol, and the functionalized solid support is a silica gel comprising 3-(1-thioureido)propyl or 3-(mercapto)propyl groups.
  • a useful intermediate for preparing a compound of formula (VII), wherein R 14 is hydrogen and R 15 is an amino-protecting group is a corresponding compound of formula (VII) wherein R 14 is an amino-protecting group that can be removed in the presence of R 15 .
  • a compound of formula (VII) wherein R 14 is hydrogen and R 15 is an amino-protecting group is itself also a useful intermediate for the preparation of a compound of formula (VII) where both R 14 and R 15 are hydrogen.
  • the invention also provides novel intermediates of formula (VII), wherein R 14 is hydrogen or an amino-protecting group, R 15 is hydrogen or an amino-protecting group, and wherein R 7 -R 13 and w have any of the values defined herein, or a salt thereof.
  • a preferred compound of formula (VII) is a compound wherein R 14 and R 15 are both hydrogen.
  • Another preferred compound of formula (VII) is a compound wherein R 14 is an alkoxycarbonyl protecting group (e.g. tert-butoxy carbonyl), and R 15 is an arylmethyl protecting group (e.g. benzyl).
  • Another preferred compound of formula (VII) is a compound wherein R 14 is hydrogen, and R 15 is an alkoxycarbonyl protecting group (e.g. tert-butoxy carbonyl).
  • the invention also provides pharmaceutical compositions comprising a compound of the invention.
  • the compound preferably in the form of a pharmaceutically-acceptable salt, can be formulated for any suitable form of administration, such as oral or parenteral administration, or administration by inhalation.
  • the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of powders, tablets, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such pharmaceutical compositions will contain from about 0.05 to about 90% by weight of the active compound, and more generally from about 0.1 to about 30%.
  • the pharmaceutical compositions may contain common carriers and excipients, such as cornstarch or gelatin, lactose, magnesium sulfate, magnesium stearate, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid.
  • Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, cornstarch, sodium starch glycolate and alginic acid.
  • a liquid composition will generally consist of a suspension or solution of the compound or pharmaceutically-acceptable salt in a suitable liquid carrier(s), for example ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, optionally with a suspending agent, a solubilizing agent (such as a cyclodextrin), preservative, surfactant, wetting agent, flavoring or coloring agent.
  • a liquid formulation can be prepared from a reconstitutable powder.
  • a powder containing active compound, suspending agent, sucrose and a sweetener can be reconstituted with water to form a suspension;
  • a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example polyvinylpyrrolidone.
  • the tablet can also be provided with a color film coating, or color included as part of the carrier(s).
  • active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures, for example by incorporation of active compound and excipients into a hard gelatin capsule.
  • a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
  • Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
  • Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
  • Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. Additionally, it may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.
  • the compounds of the invention and their pharmaceutically-acceptable salts that are active when given parenterally can be formulated for intramuscular, intrathecal, or intravenous administration.
  • a typical composition for intra-muscular or intrathecal administration will consist of a suspension or solution of active ingredient in an oil, for example arachis oil or sesame oil.
  • a typical composition for intravenous or intrathecal administration will consist of a sterile isotonic aqueous solution containing, for example active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride.
  • Other examples are lactated Ringer's injection, lactated Ringer's plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer's injection, and the like.
  • a co-solvent for example, polyethylene glycol
  • a chelating agent for example, ethylenediamine tetracetic acid
  • a solubilizing agent for example, a cyclodextrin
  • an anti-oxidant for example, sodium metabisulphite
  • the solution can be freeze dried and then reconstituted with a suitable solvent just prior to administration.
  • transdermal compositions or transdermal delivery devices (“patches”).
  • Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive.
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Pat. No. 5,023,252.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Inhalation is an effective means for delivering an agent directly to the respiratory tract.
  • inhalation devices There are three general types of pharmaceutical inhalation devices: nebulizer inhalers, dry powder inhalers (DPI), and metered-dose inhalers (MDI).
  • Nebulizer devices produce a stream of high velocity air that causes a therapeutic agent to spray as a mist which is carried into the patient's respiratory tract.
  • the therapeutic agent is formulated in a liquid form such as a solution or a suspension of micronized particles of respirable size, where micronized is typically defined as having about 90% or more of the particles with a diameter of less than about 10 ⁇ m.
  • a typical formulation for use in a conventional nebulizer device is an isotonic aqueous solution of a pharmaceutical salt of the active agent at a concentration of the active agent of between about 0.05 ⁇ g/mL and about 10 mg/mL.
  • DPI's typically administer a therapeutic agent in the form of a free flowing powder that can be dispersed in a patient's air-stream during inspiration.
  • the therapeutic agent can be formulated with a suitable excipient, such as lactose or starch.
  • a dry powder formulation can be made, for example, by combining dry lactose having a particle size between about 1 ⁇ m and about 100 ⁇ m with micronized particles of a pharmaceutical salt of the active agent and dry blending.
  • the agent can be formulated without excipients. The formulation is loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
  • DPI delivery devices examples include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g., U.S. Pat. No. 5,035,237); Diskus (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 6,378,519; Turbuhaler (AstraZeneca, Wilmington, Del.) (see, e.g., U.S. Pat. No. 4,524,769); and Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 4,353,365). Further examples of suitable DPI devices are described in U.S. Pat. Nos. 5,415,162, 5,239,993, and 5,715,810 and references therein.
  • MDI's typically discharge a measured amount of therapeutic agent using compressed propellant gas.
  • Formulations for MDI administration include a solution or suspension of active ingredient in a liquefied propellant. While chlorofluorocarbons, such as CCl 3 F, conventionally have been used as propellants, due to concerns regarding adverse affects of such agents on the ozone layer, formulations using hydrofluoroalklanes (HFA), such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3,-heptafluoro-n-propane, (HFA 227) have been developed.
  • HFA hydrofluoroalklanes
  • HFA formulations for MDI administration include co-solvents, such as ethanol or pentane, and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin.
  • co-solvents such as ethanol or pentane
  • surfactants such as sorbitan trioleate, oleic acid, lecithin, and glycerin.
  • a suitable formulation for MDI administration can include from about 0.01% to about 5% by weight of a pharmaceutical salt of active ingredient, from about 0% to about 20% by weight ethanol, and from about 0% to about 5% by weight surfactant, with the remainder being the HFA propellant.
  • chilled or pressurized hydrofluoroalkane is added to a vial containing the pharmaceutical salt of active compound, ethanol (if present) and the surfactant (if present).
  • the pharmaceutical salt is provided as micronized particles.
  • the formulation is loaded into an aerosol canister, which forms a portion of an MDI device. Examples of MDI devices developed specifically for use with HFA propellants are provided in U.S. Pat. Nos. 6,006,745 and 6,143,277.
  • a suspension formulation is prepared by spray drying a coating of surfactant on micronized particles of a pharmaceutical salt of active compound.
  • a coating of surfactant on micronized particles of a pharmaceutical salt of active compound See, for example, WO 99/53901 and WO 00/61108.
  • For additional examples of processes of preparing respirable particles, and formulations and devices suitable for inhalation dosing see U.S. Pat. Nos. 6,268,533, 5,983,956, 5,874,063, and 6,221,398, and WO 99/55319 and WO 00/30614.
  • the active compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • Suitable doses of the therapeutic agents for inhalation administration are in the general range of from about 0.05 ⁇ g/day to about 1000 ⁇ g/day, preferably from about 0.5 ⁇ g/day to about 500 ⁇ g/day.
  • a compound can be administered in a periodic dose: weekly, multiple times per week, daily, or multiple doses per day.
  • the treatment regimen may require administration over extended periods of time, for example, for several weeks or months, or the treatment regimen may require chronic administration.
  • Suitable doses for oral administration are in the general range of from about 0.05 ⁇ g/day to about 100 mg/day, preferably 0.5 to 1000 ⁇ g/day.
  • the present active agents can also be co-administered with one or more other therapeutic agents.
  • the present agents can be administered in combination with one or more therapeutic agents selected from anti-inflammatory agents (e.g. corticosteroids and non-steroidal anti-inflammatory agents (NSAIDs), antichlolinergic agents (particularly muscarinic receptor antagonists), other ⁇ 2 adrenergic receptor agonists, antiinfective agents (e.g. antibiotics or antivirals) or antihistamines.
  • anti-inflammatory agents e.g. corticosteroids and non-steroidal anti-inflammatory agents (NSAIDs)
  • antichlolinergic agents particularly muscarinic receptor antagonists
  • other ⁇ 2 adrenergic receptor agonists e.g. antibiotics or antivirals
  • antiinfective agents e.g. antibiotics or antivirals
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with one or more therapeutic agent, for example, an anti-inflammatory agent, an antichlolinergic agent, another ⁇ 2 adrenergic receptor agonist, an antiinfective agent or an antihistamine.
  • one or more therapeutic agent for example, an anti-inflammatory agent, an antichlolinergic agent, another ⁇ 2 adrenergic receptor agonist, an antiinfective agent or an antihistamine.
  • the other therapeutic agents can be used in the form of pharmaceutically acceptable salts or solvates. As appropriate, the other therapeutic agents can be used as optically pure stereoisomers.
  • Suitable anti-inflammatory agents include corticosteroids and NSAIDs.
  • Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity.
  • Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -propionyloxy-androsta-1,4-diene-17 ⁇ -carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.
  • the 17-propionate ester or the 17,21-dipropionate ester the 17-propionate ester or the 17,21-dipropionate ester
  • budesonide flunisolide
  • mometasone esters e.g. the furoate ester
  • triamcinolone acetonide e.g. the furoate ester
  • rofleponide triamcinolone acetonide
  • ciclesonide butixocort propionate
  • RPR-106541 the 17-propionate ester or the 17,21-dipropionate ester
  • ST-126 the 17-propionate ester or the 17,21-dipropionate ester
  • Preferred corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, more preferably 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • Suitable NSAIDs include sodium cromoglycate; nedocromil sodium; phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors); leukotriene antagonists (e.g. monteleukast); inhibitors of leukotriene synthesis; iNOS inhibitors; protease inhibitors, such as tryptase and elastase inhibitors; beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists); cytokine antagonists (e.g.
  • chemokine antagonists such as, an interleukin antibody ( ⁇ IL antibody), specifically, an ⁇ IL-4 therapy, an ⁇ IL-13 therapy, or a combination thereof); or inhibitors of cytokine synthesis.
  • Suitable other ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
  • PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4.
  • PDE4 inhibitor which has an IC 50 ratio of about 0.1 or greater as regards the IC 50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC 50 for the form which binds rolipram with a low affinity.
  • the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the “low affinity” binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the “high affinity” binding site (HPDE 4).
  • LPDE4 low affinity binding site
  • HPDE 4 high affinity binding site
  • the preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
  • the preferred compounds will have an IC 50 ratio of about 0.1 or greater as regards the IC 50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC 50 for the form which binds rolipram with a low affinity.
  • a further refinement of this standard is one wherein the PDE4 inhibitor has an IC 50 ratio of about 0.1 or greater; wherein said ratio is the ratio of the IC 50 value for competing with the binding of 1 nM of [ 3 H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity to the IC 50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 ⁇ M[ 3 H]-cAMP as the substrate.
  • PDE4 inhibitors which have an IC 50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
  • Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one and cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC 50 ratio of 0.1 or greater.
  • AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-I 1294A from Napp (Landells, L.
  • PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the M 1 , M 2 , or M 3 receptors, or of combinations thereof.
  • Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.
  • These drugs, particularly the salt forms are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit:
  • Atropine-CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine sulfate-CAS-5908-99-6; atropine oxide-CAS-4438-22-6 or its HCl salt-CAS-4574-60-1 and methylatropine nitrate-CAS-52-88-0.
  • Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9), anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No.
  • Suitable antihistamines include any one or more of the numerous antagonists known which inhibit HI-receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with H 1 -receptors. The majority of these inhibitors, mostly first generation antagonists, are characterized, based on their core structures, as ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines.
  • Second generation antagonists which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic a tertiary amine group with piperizine or piperidine.
  • Exemplary antagonists are as follows:
  • Ethanolamines carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
  • Ethylenediamines pyrilamine amleate, tripelennamine HCl, and tripelennamine citrate.
  • Alkylamines chlropheniramine and its salts such as the maleate salt, and acrivastine.
  • Piperazines hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl, cyclizine lactate, meclizine HCl, and cetirizine HCl.
  • Piperidines Astemizole, levocabastine HCl, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
  • Azelastine hydrochloride is yet another H 1 receptor antagonist which may be used in combination with a compound of the invention.
  • Examples of preferred anti-histamines include methapyrilene and loratadine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof and a corticosteroid.
  • the corticosteroid is fluticasone propionate or wherein the coricosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester or 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -propionyloxy-androsta-1,4-diene-17 ⁇ -carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof and a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof and an anticholinergic agent.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof and an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof together with a PDE4 inhibitor and a corticosteroid.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof together with an anticholinergic agent and a corticosteroid.
  • a compound of formula (I) includes a compound of the preferred, more preferred, or most preferred subgroup of compounds of formula (I), including a compound of formula (IIa) or (IIb) and subgroups thereof, and any individually disclosed compound or compounds.
  • compositions of the invention can optionally comprise combinations of a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof with one or more other therapeutic agents, as described above.
  • the invention provides a method of treating a disease or condition associated with ⁇ 2 adrenergic receptor activity in a mammal, comprising administering to the mammal a therapeutically effective amount of a combination of a compound of formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof with one or more other therapeutic agents.
  • This example illustrates the preparation of a representative pharmaceutical composition for oral administration of a compound of this invention: Ingredients Quantity per tablet, (mg) Active Compound 2 Lactose, spray-dried 148 Magnesium stearate 2
  • This example illustrates the preparation of another representative pharmaceutical composition for oral administration of a compound of this invention: Ingredients Quantity per tablet, (mg) Active Compound 4 Cornstarch 50 Lactose 145 Magnesium stearate 5
  • This example illustrates the preparation of a representative pharmaceutical composition for oral administration of a compound of this invention.
  • An oral suspension is prepared having the following composition. Ingredients Active Compound 0.1 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.1 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilled water q.s. to 100 mL
  • This example illustrates the preparation of a representative pharmaceutical composition containing a compound of this invention.
  • An injectable preparation buffered to a pH of 4 is prepared having the following composition: Ingredients Active Compound 0.2 g Sodium Acetate Buffer Solution (0.4 M) 2.0 mL HCl (1 N) q.s. to pH 4 Water (distilled, sterile) q.s. to 20 mL
  • This example illustrates the preparation of a representative pharmaceutical composition for injection of a compound of this invention.
  • a reconstituted solution is prepared by adding 20 mL of sterile water to 1 g of the compound of this invention. Before use, the solution is then diluted with 200 mL of an intravenous fluid that is compatible with the active compound.
  • an intravenous fluid that is compatible with the active compound.
  • Such fluids are chosen from 5% dextrose solution, 0.9% sodium chloride, or a mixture of 5% dextrose and 0.9% sodium chloride.
  • Other examples are lactated Ringer's injection, lactated Ringer's plus 5% dextrose injection, Normosol-M and 5% dextrose, Isolyte E, and acylated Ringer's injection.
  • This example illustrates the preparation of a representative pharmaceutical composition containing a compound of this invention.
  • An injectable preparation is prepared having the following composition: Ingredients Active Compound 0.1-5.0 g Hydroxypropyl- ⁇ -cyclodextrin 1-25 g 5% Aqueous Dextrose Solution (sterile) q.s. to 100 mL
  • This example illustrates the preparation of a representative pharmaceutical composition for topical application of a compound of this invention.
  • Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100
  • This example illustrates the preparation of a representative pharmaceutical composition containing a compound of the invention.
  • An aqueous aerosol formulation for use in a nebulizer is prepared by dissolving 0.1 mg of a pharmaceutical salt of active compound in a 0.9% sodium chloride solution acidified with citric acid. The mixture is stirred and sonicated until the active salt is dissolved. The pH of the solution is adjusted to a value in the range of from 3 to 8 by the slow addition of NaOH.
  • This example illustrates the preparation of a dry powder formulation containing a compound of the invention for use in inhalation cartridges.
  • Gelatin inhalation cartridges are filled with a pharmaceutical composition having the following ingredients: Ingredients mg/cartridge Pharmaceutical salt of active compound 0.2 Lactose 25
  • the pharmaceutical salt of active compound is micronized prior to blending with lactose.
  • the contents of the cartridges are administered using a powder inhaler.
  • This example illustrates the preparation of a dry powder formulation containing a compound of the invention for use in a dry powder inhalation device.
  • a pharmaceutical composition is prepared having a bulk formulation ratio of micronized pharmaceutical salt to lactose of 1:200.
  • the composition is packed into a dry powder inhalation device capable of delivering between about 10 ⁇ g and about 100 ⁇ g of active drug ingredient per dose.
  • This example illustrates the preparation of a formulation containing a compound of the invention for use in a metered dose inhaler.
  • a suspension containing 5% pharmaceutical salt of active compound, 0.5% lecithin, and 0.5% trehalose is prepared by dispersing 5 g of active compound as micronized particles with mean size less than 10 ⁇ m in a colloidal solution formed from 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 mL of demineralized water. The suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 ⁇ m. The particles are loaded into canisters with pressurized 1,1,1,2-tetrafluoroethane.
  • This example illustrates the preparation of a formulation containing a compound of the invention for use in a metered dose inhaler.
  • a suspension containing 5% pharmaceutical salt of active compound and 0.1% lecithin is prepared by dispersing 10 g of active compound as micronized particles with mean size less than 10 ⁇ m in a solution formed from 0.2 g of lecithin dissolved in 200 mL of demineralized water. The suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 ⁇ m. The particles are loaded into canisters with pressurized 1,1,1,2,3,3,3-heptafluoro-n-propane.
  • the compounds of this invention exhibit biological activity and are useful for medical treatment.
  • the ability of a compound to bind to the ⁇ 2 adrenergic receptor, as well as its selectivity, agonist potency, and intrinsic activity can be demonstrated using in vitro Tests A-C below, in vivo Test D, below, or can be demonstrated using other tests that are known in the art.
  • HEK-293 derived cell lines stably expressing cloned human ⁇ 1 or ⁇ 2 adrenergic receptors, respectively, were grown to near confluency in DMEM with 10% dialyzed FBS in the presence of 500 ⁇ g/mL Geneticin. The cell monolayer was lifted with Versene 1:5,000 (0.2 g/L EDTA in PBS) using a cell scraper. Cells were pelleted by centrifugation at 1,000 rpm, and cell pellets were either stored frozen at ⁇ 80° C. or membranes were prepared immediately.
  • cell pellets were resuspended in lysis buffer (10 mM Tris/HCL pH 7.4@4° C., one tablet of “Complete Protease Inhibitor Cocktail Tablets with 2 mM EDTA” per 50 mL buffer (Roche cat.# 1697498, Roche Molecular Biochemicals, Indianapolis, Ind.)) and homogenized using a tight-fitting Dounce glass homogenizer (20 strokes) on ice. The homogenate was centrifuged at 20,000 ⁇ g, the pellet was washed once with lysis buffer by resuspension and centrifugation as above.
  • lysis buffer 10 mM Tris/HCL pH 7.4@4° C., one tablet of “Complete Protease Inhibitor Cocktail Tablets with 2 mM EDTA” per 50 mL buffer (Roche cat.# 1697498, Roche Molecular Biochemicals, Indianapolis, Ind.)
  • the homogenate was centrifuged at 20,000 ⁇ g, the pellet was washe
  • the final pellet was resuspended in membrane buffer (75 mM Tris/HCl pH 7.4, 12.5 mM MgCl 2 , 1 mM EDTA @ 25° C.). Protein concentration of the membrane suspension was determined by the method of Bradford (Bradford MM., Analytical Biochemistry, 1976, 72, 248-54). Membranes were stored frozen in aliquots at ⁇ 80° C.
  • Binding assays were performed in 96-well microtiter plates in a total assay volume of 100 ⁇ L with 5 ⁇ g membrane protein for membranes containing the human ⁇ 2 adrenergic receptor, or 2.5 ⁇ g membrane protein for membranes containing the human ⁇ 1 adrenergic receptor in assay buffer (75 mM Tris/HCl pH 7.4@25° C., 12.5 mM MgCl 2 , 1 mM EDTA, 0.2% BSA).
  • Filter plates were washed three times with filtration buffer (75 mM Tris/HCl pH 7.4@4° C., 12.5 mM MgCl 2 , 1 mM EDTA) to remove unbound radioactivity. Plates were dried, 50 ⁇ L Microscint-20 liquid scintillation fluid (Packard BioScience Co., Meriden, Conn.) was added and plates were counted in a Packard Topcount liquid scintillation counter (Packard BioScience Co., Meriden, Conn.). Binding data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, Calif.) using the 3-parameter model for one-site competition.
  • filtration buffer 75 mM Tris/HCl pH 7.4@4° C., 12.5 mM MgCl 2 , 1 mM EDTA
  • the curve minimum was fixed to the value for nonspecific binding, as determined in the presence of 10 ⁇ M alprenolol.
  • K i values for compounds were calculated from observed IC 50 values and the K d value of the radioligand using the Cheng-Prusoff equation (Cheng Y, and Prusoff W H., Biochemical Pharmacology, 1973, 22, 23, 3099-108).
  • the receptor subtype selectivity was calculated as the ratio of K i ( ⁇ 1 )/K i ( ⁇ 2 ). All of the compounds tested demonstrated greater binding at the ⁇ 2 adrenergic receptor than at the ⁇ 1 adrenergic receptor, i.e. K i ( ⁇ 1 )>K i ( ⁇ 2 ). Most preferred compounds of the invention demonstrated a selectivity greater than about 20.
  • a HEK-293 cell line stably expressing cloned human ⁇ 2 adrenergic receptor (clone H24.14) was grown to confluency in medium consisting of DMEM supplemented with 10% FBS and 500 ⁇ g/mL Geneticin. The day before the assay, antibiotics were removed from the growth-medium.
  • cAMP assays were performed in a radioimmunoassay format using the Flashplate Adenylyl Cyclase Activation Assay System with 125 I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, Mass.), according to the manufacturers instructions.
  • a human lung epithelial cell line (BEAS-2B) was used (ATCC CRL-9609, American Type Culture Collection, Manassas, Va.) (January B, et al., British Journal of Pharmacology, 1998, 123, 4, 701-11). Cells were grown to 75-90% confluency in complete, serum-free medium (LHC-9 MEDIUM containing Epinephrine and Retinoic Acid, cat # 181-500, Biosource International, Camarillo, Calif.).
  • Test compounds were administered via inhalation over 10 minutes in a whole-body exposure dosing chamber (R&S Molds, San Carlos, Calif.). The dosing chambers were arranged so that an aerosol was simultaneously delivered to 6 individual chambers from a central manifold. Following a 60 minute acclimation period and a 10 minute exposure to nebulized water for injection (WFI), guinea pigs were exposed to an aerosol of test compound or vehicle (WFI). These aerosols were generated from aqueous solutions using an LC Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc.
  • bronchoprotective effects of compounds administered via inhalation were evaluated using whole body plethysmography at 1.5, 24, 48 and 72 hours post-dose. Forty-five minutes prior to the start of the pulmonary evaluation, each guinea pig was anesthetized with an intramuscular injection of ketamine (43.75 mg/kg), xylazine (3.50 mg/kg) and acepromazine (1.05 mg/kg). After the surgical site was shaved and cleaned with 70% alcohol, a 2-5 cm midline incision of the ventral aspect of the neck was made.
  • the jugular vein was isolated and cannulated with a saline-filled polyethylene catheter (PE-50, Becton Dickinson, Sparks, Md.) to allow for intravenous infusions of a 0.1 mg/mL solution of acetylcholine (Ach), (Sigma-Aldrich, St. Louis, Mo.) in saline.
  • Ach acetylcholine
  • the trachea was then dissected free and cannulated with a 14G teflon tube (#NE-014, Small Parts, Miami Lakes, Fla.). If required, anesthesia was maintained by additional intramuscular injections of the aforementioned anesthetic cocktail. The depth of anesthesia was monitored and adjusted if the animal responded to pinching of its paw or if the respiration rate was greater than 100 breaths/minute.
  • the animal was placed into a plethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, Conn.) and an esophageal pressure cannula was inserted to measure pulmonary driving pressure (pressure).
  • the teflon tracheal tube was attached to the opening of the plethysmograph to allow the guinea pig to breathe room air from outside the chamber. The chamber was then sealed.
  • a heating lamp was used to maintain body temperature and the guinea pig's lungs were inflated 3 times with 4 mL of air using a 10 mL calibration syringe (#5520 Series, Hans Rudolph, Kansas City, Mo.) to ensure that the lower airways had not collapsed and that the animal did not suffer from hyperventilation.
  • This signal together with the pulmonary driving pressure changes, which were collected using a Sensym pressure transducer (#TRD4T00), was connected via a Buxco (MAX 2270) preamplifier to a data collection interface (#'s SFT3400 and SFT3813). All other pulmonary parameters were derived from these two inputs.
  • the guinea pig's lungs were inflated 3 times with 4 mL of air from a 10 mL calibration syringe. Recorded pulmonary parameters included respiration frequency (breaths/minute), compliance (mL/cm H 2 O) and pulmonary resistance (cm H 2 O/nL per second) (Giles et al., 1971). Once the pulmonary function measurements were completed at minute 35 of this protocol, the guinea pig was removed from the plethysmograph and euthanized by CO 2 asphyxiation.
  • C 2 Final concentration of Ach (concentration resulting in a 2-fold increase in pulmonary resistance (R L ))
  • X is the logarithm of dose
  • Y is the response (PD 2 )
  • Y starts at Min and approaches asymptotically to Max with a sigmoidal shape.
  • the mixture was shaken and heated at 80° C. for 5 hours.
  • Acetic acid (80% aq., 0.6 mL) was added and the mixture was shaken and heated at 80° C. for 5 hours.
  • the crude reaction was diluted to a total volume of 2 mL with DMF, filtered, and purified by reversed phase HPLC, using a mass-triggered, automated collection device.
  • the product containing fractions were analyzed by analytical LC-MS, and freeze-dried to give a TFA salt of compound 1 as a powder.
  • the mixture was diluted with 200 mL diethyl ether and washed twice with 100 mL portions of 1.0 M aqueous NaHSO 4 , followed by 100 mL of saturated aqueous NaHCO 3 .
  • the diethyl ether phase was dried over MgSO 4 , filtered, and concentrated to a dark oil.
  • the oil was purified by silica gel chromatography (gradient of 30 to 40% ethyl acetate in hexanes) to afford compound dd as a yellow foam (2.5 g, 51%).
  • the reaction was concentrated and the residue was diluted with 30 mL water and extracted twice with 30 mL portions of toluene. The toluene extracts were combined, dried over Na 2 SO 4 , filtered, and concentrated. The residue was heated to 120° C. After 13 h, the reaction was cooled to room temperature and the crude compound dd was carried on to the next step without purification.
  • the intermediate bromohydrin GG can be prepared as described in U.S. Pat. No. 6,268,533 BI; and in R. Hett et al., Organic Process Research and Development, 1998, 2, 96-99.
  • the intermediate bromohydrin GG can also be prepared using procedures similar to those described by Hong et al., Tetrahedron Lett., 1994, 35, 6631; or similar to those described in U.S. Pat. No. 5,495,054.
  • the mixture was diluted with 200 mL methylene chloride and washed with 100 mL of saturated aqueous NaHCO 3 , followed by 100 mL saturated aqueous NaCl.
  • the organic phase was dried over MgSO 4 , filtered, and concentrated.
  • the oil was purified by silica gel chromatography (gradient of 0 to 5% methanol in methylene chloride) to afford compound hh as an orange solid.
  • the intermediate epoxide P can be prepared as described in International Patent Application Publication Number WO 95/25104; and as described in EP 0 147 719 A2 and EP 0 147 791 B.
  • the intermediate compound F was prepared as follows.
  • the mixture was partitioned between 1.0 M aqueous NaHSO 4 and diethyl ether, and the phases were separated.
  • the diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHSO 4 and brine, dried over Na 2 SO 4 , filtered, and concentrated to a dark oil.
  • the oil was purified by chromatography, using 15% EtOAc/85% hexanes as eluent, to give 2.52 g (73%) of compound C as a dark orange oil.
  • the intermediate epoxide a can be prepared as described by R. Hett et al., Tetrahedron Lett., 1994, 35, 9357-9378.
  • the intermediate compound Q was prepared as follows.
  • the mixture was partitioned between 1.0 M aqueous NaHSO 4 and diethyl ether.
  • the diethyl ether phase was washed once each with saturated NaHCO 3 and brine, dried over MgSO 4 , filtered, and concentrated to a dark oil.
  • the oil was purified by silica gel chromatography, using 15% EtOAc/85% hexanes as eluant, to give compound Y as a dark orange oil.
  • the mixture was partitioned between 1.0 M aqueous NaHSO 4 and diethyl ether, and the phases were separated.
  • the diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHSO 4 and brine, dried over Na 2 SO 4 , filtered, and concentrated to a dark oil.
  • the oil was purified by silica gel chromatography, using 12% EtOAc/88% hexanes as eluent, to give compound D as a yellow foam.
  • the intermediate compound N was prepared as follows.
  • the mixture was partitioned between 1.0 M aqueous NaHSO 4 and diethyl ether, and the phases were separated.
  • the diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHSO 4 and brine, dried over Na 2 SO 4 , filtered, and concentrated to a dark oil.
  • the oil was purified by silica gel chromatography, using 10% EtOAc/90% hexanes as eluent, to give 4.13 g (77%) of compound L as a yellow foam.
  • the intermediate epoxide b can be prepared as described in U.S. Pat. No. 6,268,533 B1, and in R. Hett. et al., Organic Process Research and Development, 1998, 2, 96-99.
  • the intermediate compound 0 was prepared as follows.
  • TFA salt 75 mg was dissolved in acetonitrile (1.0 mL) and diluted with water (2.0 mL) followed by 0.1 N HCl (3.0 mL). The solution became cloudy. Addition of 1.5 mL acetonitrile afforded a clear solution which was frozen and lyophilized. The residue was redissolved in acetonitrile (1.0 mL) and diluted with water (2.0 mL) followed by 0.1 N HCl (4.0 mL). The solution became cloudy. Addition of 1.0 mL acetonitrile afforded a clear solution which was frozen and lyophilized.
  • the intermediate compound S was prepared as follows.
  • the intermediate bromoketone R can be prepared as described in Example 611B, parts a-d. See also EP 0 147 791 B.
  • the intermediate jj was prepared as follows.
  • the mixture was stirred at 95° C. for 6 h under a nitrogen atmosphere.
  • the mixture was diluted with 200 mL diethyl ether and washed twice with 100 mL portions of 1.0 M aqueous NaHSO 4 , followed by 100 mL of saturated aqueous NaHCO 3 .
  • the diethyl ether phase was dried over MgSO 4 , filtered, and concentrated to a dark oil.
  • the oil was purified by silica gel chromatography (gradient of 30 to 40% ethyl acetate in hexanes) to afford compound cc as an orange foam.
  • the intermediate PP was prepared as follows:
  • the product (1.14 g, 1.65 mmol) was solubilized in 12 mL THF/EtOH (1:1) and NaBH 4 (380 mg, 10.0 mmol) was added. After 20 minutes of vigorous stirring. The reaction was quenched with saturated aqueous NH 4 Cl which was added until effervescence of the reaction mixture ceased. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed twice with saturated sodium bicarbonate, followed by saturated sodium chloride, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2% MeOH in CH 2 Cl 2 ) to yield 230 mg of intermediate rr.
  • the intermediate compound V was prepared as follows.
  • o-Xylene 50 ntL was added, and the solution was heated at reflux under nitrogen for 2.5 hours, at which time HPLC analysis indicated complete reaction.
  • the o-xylene was removed under vacuum with heating, and dichloromethane (200 mL) was added. Once the residue was dissolved, celite (30 g) was added, and the mixture was filtered and filter cake was washed with dichloromethane until all of the product was collected.
  • the solution was concentrated to dryness under vacuum, redissolved in THF (20 mL), and purged with nitrogen. Tetrabutylammonium fluoride (20 mL, 1.0 M in THF, 20 mmol) was added via syringe, and the solution was stirred for 18 hours at room temperature.
  • Compound 72 Formula (X) where R 11 is 4-pyridyl: 1 H NMR (300 MHz, DMSO-d6) ⁇ 10.48 (s, 1H) 10.38 (s, 1H), 8.60 (br m, 4H), 8.32 (s, 1H), 8.07 (d, 1H), 7.69 (d, 2H), 7.31 (m, 2H), 7.16 (d, 1H) 7.05 (m, 6H), 6.90 (d, 1H), 6.52 (dd, 1H), 6.11 (s, 1H), 5.24 (d, 1H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H + ] calcd for C 30 H 28 N 4 O 3 493.23; found 493.5.
  • Compound 75 Formula (X) where R 11 is trans-2-phenylvinyl: m/z: [M+H + ] calcd for C 33 H 31 N 3 O 3 518.25; found 518.3.
  • Compound 78 Formula (X) where R 11 is 3,5-dimethylisoxazole-4-yl: m/z: [M+H + ] calcd for C 30 H 30 N 4 O 4 511.24; found 511.5.
  • Compound 80 Formula (X) where R 11 is thiophene-2-yl: 1 H NMR (300 MHz, DMSO-d6) ⁇ 10.47 (s, 1H), 10.38 (s, 1H), 8.62 (br s, 2H), 8.22 (s, 1H), 8.07 (d, 1H), 7.44 (d, 11H), 7.33 (d, 1H), 7.35 (m, 2H), 7.06 (m, 7H), 6.90 (d, 2H), 6.50 (d, 11H), 6.10 (d, 11H), 5.23 (m, 1H), 3.10 (m, 4H), 2.85 (m, 2H). m/z [M+H + ] calcd for C 29 H 27 N 3 O 3 S 498.19; found 498.5.
  • Compound 83 Formula (X) where R 11 is 2-pyrrolyl: Using a procedure similar to that described in Example 74, except replacing the 3-cyanophenylboronic acid with 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid, a TFA salt of compound 83 was prepared. Deprotection of the Boc group occurred under reaction conditions.
  • Compound 86 Formula (X) where R 11 is 4-hydroxyphenyl: Using a procedure similar to that described in Example 74, except replacing the 3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA salt of compound 86 was prepared.

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US10/431,762 US20030229058A1 (en) 2001-11-13 2003-05-08 Aryl aniline beta2 adrenergic receptor agonists
JP2006514309A JP2006525372A (ja) 2003-05-08 2004-05-07 アリールアニリンβ−２アドレナリン作用性レセプタアゴニストおよびコルチコステロイドの組み合わせ
AT04809361T ATE447408T1 (de) 2003-05-08 2004-05-07 Kombinationen aus einem arylanilin-beta-2- adrenozeptor-agonisten und einem corticosteroid
EP04809361A EP1641465B1 (en) 2003-05-08 2004-05-07 Combinations of an aryl aniline beta-2 adrenergic receptor agonist and a corticosteroid
PCT/US2004/014168 WO2005025555A2 (en) 2003-05-08 2004-05-07 Combinations of an aryl aniline beta-2 adrenergic receptor agonist and a corticosteroid
DE602004023946T DE602004023946D1 (de) 2003-05-08 2004-05-07 Kombinationen aus einem arylanilin-beta-2-adrenozeptor-agonisten und einem corticosteroid
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ATE447408T1 (de) 2009-11-15
WO2005025555A3 (en) 2005-06-23
WO2005025555A2 (en) 2005-03-24
US20070225329A1 (en) 2007-09-27
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