US20040054187A1 - Therapeutic ureas - Google Patents

Therapeutic ureas Download PDF

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US20040054187A1
US20040054187A1 US10/426,364 US42636403A US2004054187A1 US 20040054187 A1 US20040054187 A1 US 20040054187A1 US 42636403 A US42636403 A US 42636403A US 2004054187 A1 US2004054187 A1 US 2004054187A1
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Mathai Mammen
David Oare
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Theravance Biopharma R&D IP LLC
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Mathai Mammen
David Oare
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems

Definitions

  • a receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences.
  • Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
  • a ligand is a binding partner for a specific receptor or family of receptors.
  • a ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
  • the G-proteins when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).
  • Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family of five receptor sub-types (M 1 , M 2 , M 3 , M 4 and M 5 ) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I. et al., Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med., 1989, 321, 1022; Hulme, E.
  • the smooth muscle is composed largely of M 2 and M 3 receptors
  • cardiac muscle is composed largely of M 2 receptors
  • salivary glands are largely composed of M 3 receptors.
  • muscarinic receptors are involved in diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A., Invest. Drugs, 1997, 6(10), 1395-141 1; Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137; Graul, A. and Castaner, J., Drugs Future, 1996, 21(11), 1105-1108; and Graul, A., et al., Drugs Future, 1997, 22(7), 733-737).
  • diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis,
  • a number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases.
  • oxybutynin is being used for the treatment of urinary urge incontinence
  • dicyclomine is being used for the treatment of irritable bowel syndrome.
  • these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis.
  • the invention is directed to urea derivatives that are muscarinic receptor antagonists and agonists and that are useful in the treatment and prevention of diseases mediated by muscarinic receptors (e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like).
  • diseases mediated by muscarinic receptors e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
  • the invention provides a compound of the invention which is a compound of Formula (I):
  • L 1 is a group of formula (a):
  • A is an aryl or a heteroaryl ring
  • B′′ is —NR a — wherein R a is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
  • R 1 is hydrogen or alkyl
  • R 2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii):
  • n 1 is an integer of from 1 to 4.
  • n 2 is an integer of from 1 to 3;
  • V is —CH—, —O—, —S(O)n 3 — (where n 3 is an integer of from 0 to 2), or —NR 4 —(wherein R 4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
  • Het is a heteroaryl ring which optionally attaches (a) to a linker
  • R 3 is hydrogen, alkyl, amino, substituted amino, —OR a (where R a is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
  • R 5 is hydrogen, alkyl, amino, substituted amino, —OR b (where R b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
  • R 6 , R 7 , and R 8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
  • K is a bond or an alkylene group
  • K′′ is a bond, —C(O)—, —S(O) n4 —(where n 4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group;
  • B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;
  • R 5 , R 6 , R 7 , R 8 , “Het”, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
  • X is a linker
  • L 2 is a group selected from a group consisting of:
  • D′′ is alkylene
  • D is —NR 31 R 32 , —N + (R 33 R 34 R 35 ) or—OR 32 where R 31 , R 33 , and R 34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R 32 and R 35 represent a covalent bond attaching (b) to a linker;
  • R 27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
  • R 28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
  • R 29 and R 30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or
  • R 27 , R 28 , R 29 , or R 30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group
  • n 11 is an integer of from 1 to 7;
  • n 12 is 0 to 7;
  • F is —NR 40 —, —O—, —S—, or —CHR 41 — (wherein R 40 and R 41 are, independently of each other, hydrogen, alkyl, or substituted alkyl);
  • F′′ is a covalent bond, —OR 43 , —NR 42 R 43 , or —N + R 43 R 44 R 45 wherein R 42 is hydrogen or alkyl, R 44 and R 45 are alkyl, and R 43 is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
  • R 36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
  • R 37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and
  • R 38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R 38 and R 43 attaches (c) to a linker;
  • R 39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl
  • R 46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;
  • R 47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR 50 where R 50 is alkyl; or
  • one or more e.g. 1, 2, 3, or 4
  • R 48 is a covalent bond that attaches the (d) or the (e) to a linker
  • R 49 is alkyl
  • X is a group of formula:
  • m is an integer of from 0 to 20;
  • X a at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
  • Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
  • Y a and Y b at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′C(O)—, —NR′ C(O)NR′—, —NR′C(S)NR′—, —C( ⁇ NR′)—NR′—, —NR′—C( ⁇ NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N ⁇ C(R′′)—NR′—, —NR′—C(R′′) ⁇ N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O) n CR′R′′—, —S(O) n —NR′—, —NR′—S(O)
  • the invention also provides a compound of the invention which is a compound of formula (IV):
  • R 2 , K′′, A, K, R 1 , B′′, B, X, and L 2 have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof.
  • a preferred compound of the invention is a compound of formula (IVa):
  • X, and L 2 have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
  • the invention also provides synthetic intermediates disclosed herein, as well as synthetic methods useful for preparing such intermediates, and synthetic methods useful for preparing compounds of the invention or salts thereof.
  • the invention also provides a method of treating diseases mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
  • the invention also provides a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for use in medical therapy, as well as the use of a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a disease mediated by a muscarinic receptor in a mammal.
  • urea compounds of the present invention are metabolically more stable than compounds lacking such a urea functionality. Accordingly, compounds of the present invention have longer metabolic half-lives and/or longer duration of action in vivo, which can reduce the dose required for administration or can reduce the likelihood of the generation of unwanted metabolites.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • substituted alkyl refers to an alkyl group as defined above wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as —O—, —S(O)n— (where n is 0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thio
  • This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminoprppyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), the propylene isomers (e.g., —CH 2 CH 2 CH 2 — and —CH(CH 3 )CH 2 —) and the like.
  • substituted alkylene refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alk
  • substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • fused groups contain from 1 to 3 fused ring structures.
  • alkylaminoalkyl refers to the groups R a NHR b — where R a is alkyl group as defined above and R b is alkylene, alkenylene or alkynylene group as defined above.
  • R a is alkyl group as defined above
  • R b is alkylene, alkenylene or alkynylene group as defined above.
  • Such groups are exemplified by 3-methylaminobutyl, 4-ethylamino-1,1-dimethylbutyn-1-yl, 4-ethylaminobutyn-1-yl, and the like.
  • alkaryl or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • alkoxy refers to the groups alkyl-O—, alkenyl-O—, cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • Preferred alkoxy groups are alkyl-O— and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • substituted alkoxy refers to the groups substituted alkyl-O—, substituted alkenyl-O—, substituted cycloalkyl-O—, substituted cycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • haloalkoxy refers to the groups alkyl-O— wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (—CH 2 OCH 3 ), ethylenemethoxy (—CH 2 CH 2 OCH 3 ), n-propylene-iso-propoxy (—CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (—CH 2 —O—C(CH 3 ) 3 ), and the like.
  • alkylthioalkoxy refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (—CH 2 SCH 3 ), ethylenethiomethoxy (—CH 2 CH 2 SCH 3 ), n-propylene-iso-thiopropoxy (—CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ), methylene-t-thiobutoxy (—CH 2 SC(CH 3 ) 3 ), and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation.
  • Preferred alkenyl groups include ethenyl (—CH ⁇ CH 2 ), n-propenyl (—CH 2 CH ⁇ CH 2 ), iso-propenyl (—C(CH 3 ) ⁇ CH 2 ), and the like.
  • substituted alkenyl refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alk
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation.
  • This term is exemplified by groups such as ethenylene (—CH ⁇ CH—), the propenylene isomers (e.g., —CH 2 CH ⁇ CH— or —C(CH 3 ) ⁇ CH—), and the like.
  • substituted alkenylene refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, amninoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamin
  • substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynyl groups include ethynyl (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), and the like.
  • substituted alkynyl refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino,
  • alkynylene refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynylene groups include ethynylene (—CE ⁇ C—), propargylene (—CH 2 C ⁇ C—), and the like.
  • substituted alkynylene refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, arninoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxya
  • acyl refers to the groups HC(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • acylamino or “aminocarbonyl” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • aminoacyl refers to the group —NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • aminoacyloxy or “alkoxycarbonylamino” refers to the group —NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryl
  • aryloxy refers to the group aryl-O— wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
  • arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
  • amino refers to the group —NH 2 .
  • substituted amino refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic provided that both R's are not hydrogen.
  • carboxyalkyl or “alkoxycarbonyl” refers to the groups “—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”, “—C(O)O-substituted cycloalkyl”, “—C(O)O-alkenyl”, “—C(O)O-substituted alkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alk
  • cycloalkenyl refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino,
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano,
  • Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • heteroaralkyl refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. Such heteroaralkyl groups are exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
  • heteroaryloxy refers to the group heteroaryl-O—.
  • heteroarylene refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like.
  • heterocycle or “heterocyclic” or refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro
  • nitrogen heteroaryls and heterocycles include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofuranyl, tetra
  • heterocyclooxy refers to the group heterocyclic-O—.
  • thioheterocyclooxy refers to the group heterocyclic-S—.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morpholino and the like.
  • Heteroarylamino means a 5 membered aromatic ring wherein one or two ring atoms are N, the remaining ring atoms being C.
  • the heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, —OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or —S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl
  • Heterocycloamino means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl].
  • heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, indolino, or thiomorpholino.
  • heterocycloamino also includes, quinuclidine, 1 -azabicyclo[2.2.1]heptyl, 1-azabicyclo[3.2.1]octyl and the derivatives thereof.
  • oxyacylamino or “aminocarbonyloxy” refers to the group —OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • spiro-attached cycloalkyl group refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.
  • thiol refers to the group —SH.
  • thioalkoxy or “alkylthio” refers to the group —S-alkyl.
  • substituted thioalkoxy refers to the group —S-substituted alkyl.
  • thioaryloxy refers to the group aryl-S— wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
  • heteroaryloxy refers to the group heteroaryl-S— wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
  • any of the above groups which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • pharmaceutically-acceptable salt refers to salts which retain biological effectiveness and are not biologically or otherwise undesirable.
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Salts derived from inorganic bases include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cyclo
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically-acceptable cation refers to the cation of a pharmaceutically-acceptable salt.
  • protecting group refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like.
  • Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product.
  • Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product.
  • inert organic solvent or “inert organic solvent” means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like.
  • the solvents used in the reactions described herein are inert solvents.
  • treatment refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes:
  • pathologic condition which is modulated by treatment with a ligand covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the muscarinic receptors in general, and those disease states which have been found to be usefully treated by a compound of the invention.
  • disease states include, by way of example only, the treatment of a mammal afflicted with chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
  • therapeutically effective amount refers to that amount of a compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • linker refers to a group or groups that covalently attaches L 1 and L 2 . Additionally, the linker can be either a chiral or achiral molecule.
  • linker does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the compounds of this invention can be attached to a solid support if desired. For example, such attachment to solid supports can be made for use in separation and purification processes and similar applications.
  • Pro-drugs means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs include compounds of Formula (D) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • a preferred value for A is phenyl or pyridine
  • a preferred value for R 1 is hydrogen methyl, or ethyl.
  • R 1 Another preferred value for R 1 is hydrogen.
  • R 2 is pyrrolyl, pyridinyl, or imidazolyl.
  • R 2 Another preferred value for R 2 is phenyl.
  • V is —CH— or —NR 4 — (wherein R 4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl).
  • R 3 is hydrogen or alkyl
  • R 5 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker
  • R 5 is hydrogen, methyl, phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino.
  • a preferred value for R 6 , R 7 , and R 8 independent of each other is hydrogen, alkyl, nitro, hydroxy, or amino.
  • a preferred value for K is alkylene having from 1 to 10 carbon atoms.
  • a preferred value for K is alkylene having from 1 to 5 carbon atoms.
  • a preferred value for K is a bond or a methylene group.
  • a preferred value for K′′ is a bond.
  • a preferred value for R a is hydrogen.
  • a preferred value for B is a heterocycloamino group which attaches (a) to a linker.
  • Another preferred value for B is a formula selected from a group consisting of formula (j), formula (k), and formula (l):
  • n 13 and n 14 are, independently of each other, an integer of from 0 to 4 provided that n 13 +n 14 is an integer of from 3 to 5;
  • n 15 and n 17 are, independently of each other, an integer of from 0 to 4 provided that n 15 +n 17 is an integer of from 3 to 5;
  • n 16 is an integer of from 0 to 3 provided that n 15 +n 16 is an integer of from 3 to 5;
  • n 18 , n 19 and n 20 are, independently of each other, an integer of from 0 to 3 provided that n 18 +n 19 +n 20 is 2 or 3;
  • n 21 is an integer of from 1 to 3;
  • W a and W c are, independently of each other:
  • n 22 is 0 or 1;
  • R 53 and R 54 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl or a covalent bond attaching (a) to a linker;
  • R 55 is alkyl, alkenyl or alkynyl
  • W b is —N(O)n 23 or —N + —R 56 where n 23 is 0 or 1, and R 56 is alkyl, alkenyl, alkynyl, or aralkyl, or a covalent bond attaching (a) to a linker;
  • Another preferred value for B is a ring represented by the following general formulae:
  • a more preferred value for B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker.
  • Another more preferred value for B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.
  • Another more preferred value for B is piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.
  • B Another more preferred value for B is quinuclidine, 1-azabicyclo[2.2.1]-heptyl, or 1-azabicyclo[3.2.1]octyl attaching (a) to a linker, wherein a carbon other than a bridge head carbon is bound to B′′.
  • a preferred value for D′′ is —(CH 2 )n 43 — where n 43 is an integer of from 1-10, preferably 2-8, more preferably 2-4. Another preferred value for n 43 is an integer of from 3-10.
  • a preferred value for D is —NR 31 R 32 or —N + (R 33 R 34 R 35 )M ⁇ where R 31 , R 33 , and R 34 are, independently of each other, hydrogen or methyl, and R 32 and R 35 represent a covalent bond attaching (b) to a linker. More preferably R 31 , R 33 , and R 34 methyl, and R 32 and R 35 represent a covalent bond attaching (b) to a linker.
  • a preferred value for R 27 is hydrogen.
  • a preferred value for R 28 is hydrogen.
  • R 29 and R 30 independently is hydrogen; or one of R 27 , R 28 , R 29 , or R 30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group.
  • n 11 A preferred value for n 11 is 1.
  • a preferred value for n 12 is 6.
  • a preferred value for F is —O—.
  • a preferred value for F′′ is a covalent bond, —OR 43 , —NR 42 R 43 wherein R 42 is hydrogen or alkyl, or —N + (R 43 R 44 R 45 ) wherein R 44 and R 45 are alkyl, and R 43 is a covalent bond attaching (c) to a linker.
  • a preferred value for F′′ is —O—, —NH—, N(CH 3 )— or —N(CH 3 ) 2 —
  • a more preferred value for F′′ is —NH—, N(CH 3 )— or —N(CH 3 ) 2 — wherein the nitrogen atom attaches (c) to a linker.
  • a preferred value for R 36 is hydrogen.
  • R 37 is ortho to the —(CHR 38 )— group and is hydrogen or alkoxy. More preferably R 37 is ortho to the —(CHR 38 )— group and is methoxy.
  • R 38 is hydrogen
  • R 39 is hydrogen
  • L 2 is a group of formula (d) wherein: R 46 is alkyl or substituted alkyl; R 47 is alkyl, substituted alkyl, or heterocycle; or R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle.
  • L 2 is a group of formula A1-A241 as shown in the following table.
  • L 2 is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L 2 . No.
  • L 2 can also be a group of formula A301-A439 as shown in the following table.
  • L 2 is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L 2 .
  • L 2 can also be a group of formula A501-A523 as shown in the following table.
  • L 2 is preferably linked to X through a non-aromatic nitrogen atom of L 2 .
  • No. L 2 A501 A502 A503 A504 A505 A506 A507 A508 A509 A510 A511 A512 A513 A514 A515 A516 A517 A518 A519 A520 A521 A522 A523 A524 A525 A526 A527 A528 A529 A530 A531 A532 A533 A534 A535 A536 A537 A538 A539 A540 A541 A542 A543 A544 A545 A546 A547 A548 A549 A550 A551 A552 A553 A554 A555 A556 A557 A558 A559 A560 A561 A562 A563 A564 A565 A566 A567 A5
  • a more preferred value for L 2 is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.
  • a preferred value for X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
  • Another preferred value for X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, or 4) in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4).
  • Another preferred value for X is an alkylene group having from 6 to 15 carbons atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, 4) in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4).
  • Another preferred value for X is is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
  • a preferred group of compounds of formula (I) are compounds wherein R 2 is selected from formula (i) and (iii); and wherein K′′ is a bond or methylene.
  • a preferred group of compounds of formula (I) are compounds wherein R 2 is formula (i); R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and K′′ is a bond or methylene.
  • a preferred group of compounds of formula (I) are compounds wherein R 2 is formula (iii); R 6 , R 7 , and R 8 are each hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and K′′ is a bond or methylene.
  • a preferred group of compounds are compounds of formula (I) wherein R 46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R 47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR 50 where R 50 is alkyl; or R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle.
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic
  • a more preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • a preferred group of compounds are compounds of formula (I) wherein L is a group of formula (d) wherein at least one of R 46 and R 47 individually, or R 46 and R 47 taken together, is a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • L is a group of formula (d) wherein at least one of R 46 and R 47 individually, or R 46 and R 47 taken together, is a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and R 47 is alkyl, substituted alkyl, acyl, or —COOR 50 .
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 is alkyl that is substituted by a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • a basic nitrogen atom e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7.
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NR a R b , wherein R a and R b may be the
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamin
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R 46 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxy
  • a preferred group of compounds are compounds of formula (I) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted
  • a preferred group of compounds are compounds of formula (I) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).
  • aza-crown ether e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).
  • a preferred group of compounds of formula (I) are compounds wherein: A is an aryl or a heteroaryl ring; B′′ is —NRa— wherein Ra is hydrogen, alkyl, or substituted alkyl; R 1 is hydrogen or alkyl; R 2 is selected from a group consisting of formula (i), (ii), (iii), or “Het”:
  • n is an integer of from 1 to 4; n 2 is an integer of from 1 to 3; V is —CH—, —O—, —S(O)n 3 — (where n 3 is an integer of from 0 to 2), or —NR 4 — (wherein R 4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); “Het” is a heteroaryl ring which optionally attaches the ligand to a linker; R 3 is hydrogen, alkyl, amino, substituted amino, —OR 8 (where R a is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker; R 5 is hydrogen, alkyl, amino, substituted amino, —OR b (where R b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand
  • a preferred compound of formula (I) is a compound of Formula (Ia):
  • a preferred group of compounds is that wherein A is phenyl or pyridine; and K and K′′ are bond.
  • the invention also provides a compound of formula (IV):
  • L 2 is an organic group comprising at least one (e.g. 1, 2, 3, or 4) primary, secondary, or tertiary amines.
  • the amine of L 2 should be basic, having a pH of at least about 5, and preferably at least about 6, more preferably at least about 7.
  • the nature of the group L 2 is not critical provided the compound has suitable properties (e.g. solubility, stability, and toxicity) for its intended use (e.g. as a drug or as a pharmacological tool).
  • the group L 2 will have a molecular weight below 500 and preferably below about 300.
  • the group L 2 preferably comprises 5 or fewer hydrogen bond donors (e.g.
  • the nitrogen of B shown in formula (IV) is separated from an amine of the group L 2 by about 15 angstroms to about 75 angstroms (based on conventionally acceptable bond lengths and angles). More preferably, the nitrogen of B is separated from an amine of the group L 2 by about 25 angstroms to about 50 angstroms.
  • Preferred compounds of formula (IV) also have a log D between about ⁇ 3 and about 5. Using the above parameters, one skilled in the art can readily determine compounds of formula (IV) possessing the desired properties for an intended use.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., U.S.A.), Bachem (Torrance, Calif., U.S.A.), Emka-Chemie, or Sigma (St.
  • the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • a compound of Formula (I) is prepared by covalently attaching one equivalent of a compound of formula 1 with a compound of formula 2 where X is a linker as defined herein, FG 1 is a functional group, FG 2 is a functional group that is complimentary to FG 1 , PG is a protecting group, and FG 2 PG is a protected functional group, to give an intermediate of formula (II).
  • X is a linker as defined herein
  • FG 1 is a functional group
  • FG 2 is a functional group that is complimentary to FG 1
  • PG is a protecting group
  • FG 2 PG is a protected functional group
  • Suitable dihydroxyl and dihalo starting materials useful for incorporating a group X into a compound of the invention are shown in the following table.
  • an alcohol is reacted with a ligand bearing a leaving group to provide an ether bond
  • a dihalo compound is preferably reacted with an amine of the ligand to form a subatituted amine.
  • a compound selected for use as a ligand will have at least one functional group, such as an amino, hydroxyl, thiol or carboxyl group and the like, which allows the compound to be readily coupled to the linker.
  • functional group such as an amino, hydroxyl, thiol or carboxyl group and the like.
  • a compound of formula (a) wherein A is phenyl, pyridyl, and the like can be prepared as described in EP 747 355 and as described by Naito, R. et al., Chem. Pharm. Bull., 1998, 46(8), 1286.
  • a compound of formula (I) wherein L 1 comprises a nitrogen that is bonded to X can be prepared by alkylating a corresponding compound of formula L 1 —H wherein —H is bound to the nitrogen, with a corresponding compound of R a —X—L 2 wherein X and L 2 have any of the values defined herein and R a is a suitable leaving group.
  • Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York.
  • R a can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
  • the invention provides a method for preparing a compound of formula (I) wherein L 1 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L 1 —H with a compound of R a —X—L 2 wherein X and L 2 have any of the values defined herein and R a is a suitable leaving group.
  • the invention also provides a compound of formula L 1 —H wherein L 1 has any of the values defined herein.
  • L 1 has any of the values defined herein.
  • the following compounds are preferred compounds of formula L 1 —H:
  • the invention also provides a compound of formula R a —X—L 2 wherein X, and L 2 have any of the values defined herein and R a is a suitable leaving group.
  • the compound of formula L 1 —H can also be alkylated by treatment with an aldehyde of formula L 2 —V—CHO (wherein —V—CH 2 — is equivalent to —X—), under reductive alkylation conditions.
  • Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).
  • the invention provides a method for preparing a compound of formula (I) wherein L 1 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L 1 —H with a compound of formula L 2 —V—CHO (wherein —V—CH 2 — has any of the values for —X— described herein).
  • a compound of formula (I) wherein L 2 comprises a nitrogen that is bonded to X can be prepared by alkylating a corresponding compound of formula L 2 —H wherein —H is bound to the nitrogen, with a corresponding compound of L 1 —X—R a wherein X and L 1 have any of the values defined herein and R a is a suitable leaving group.
  • Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York.
  • R a can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
  • the invention provides a method for preparing a compound of formula (I) wherein L 2 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L 2 —H with a compound of L 1 —X—R a wherein X and L 1 have any of the values defined herein and R a is a suitable leaving group.
  • the compound of formula L 2 —H can also be alkylated by treatment with an aldehyde of formula L 1 —V—CHO (wherein —V—CH 2 — is equivalent to —X—), under reductive alkylation conditions.
  • an aldehyde of formula L 1 —V—CHO wherein —V—CH 2 — is equivalent to —X—
  • Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).
  • the invention provides a method for preparing a compound of formula (I) wherein L 2 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L 2 —H with a compound of formula L 1 —V—CHO (wherein —V—CH 2 — has any of the values for —X— described herein).
  • the invention provides a method for preparing a compound of formula (I) comprising deprotecting a corresponding compound of formula (I) that bears one or more protecting groups.
  • the invention also provides an intermediate compound of formula (I) that bears one or more protecting groups.
  • Compounds of formula (I) can conveniently be prepared using combinatorial synthesis methods (e.g. solid phase and solution phase combinatorial synthesis methods) that are known in the art.
  • combinatorial synthesis methods e.g. solid phase and solution phase combinatorial synthesis methods
  • compounds of formula (I) can be prepared using combinatorial methods like those escribed in International Patent Application Publication Number WO 99/64043.
  • the compounds of this invention are muscarinic receptor antagonists or agonists.
  • a preferred sub-groug of compounds of the invention are M 2 muscarinic receptor antagonists.
  • the compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by these receptors such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, hyper salvation syndromes, and the like.
  • a muscarinic receptor e.g. the M 2 or M 3 subtype
  • a muscarinic receptor e.g. the M 2 or M 3 subtype
  • the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intravesicular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, usually about 0.1 to about 500 mg, more usually about 1 to about 50 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compound of Formula (I) above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically 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.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insulation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Biphenyl-2-isocynate 50 g, 256 mmol was dissolved in 400 mL anhydrous acetonitrile in a 2L rbf at room temperature. After cooling to 0 C. using an ice bath, a solution of 4-amino-N-benzylpiperidine (48.8 g, 256 mmol) dissolved in 400 mL anhydrous acetonitrile was added over 5 minutes. Precipitate was observed immediately. After 15 minutes, an additional 600 mL anhydrous acetonitrile was added to permit stirring of the viscous solution for 12 h at 35 C. The solids were filtered, and washed with cold acetonitrile then dried under vacuum, yielding a colorless solid (100 g, 98%). This material was characterized by 1 H-NMR, 13 C-NMR and MS.
  • Hard gelatin capsules containing the following ingredients are prepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate 5.0
  • a tablet Formula is prepared using the ingredients below: Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0
  • a dry powder inhaler formulation is prepared containing the following components: Ingredient Weight % Active Ingredient 5 Lactose 95
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50° to 60° C. and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg
  • Suppositories each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 mL dose are made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 mL
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a formulation may be prepared as follows: Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg
  • a formulation may be prepared as follows: Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL
  • transdermal delivery devices Such 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, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated by reference in its entirety.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • SF9 cell membranes containing human M 2 muscarinic receptor was obtained from NEN (Boston, Mass.). In 96-well microtiter plates, eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 ⁇ M (4 ⁇ the final concentration). To 100 ⁇ l of compound dilution was added 150 ⁇ L M 3 receptor membrane preparation in PBS/1.0 mM MgCl 2 /pH 7.4. 50 ⁇ l of 3.2 nM 3H-N-methylscopolamine radioligand was added. The total volume in each well was then 300 ⁇ l.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 minutes, and then washed twice with 200 ⁇ l PBS.
  • the assay plate was incubated for 1 hour at room temperature with gentle shaking. The contents of the assay plate were then transferred to the filter plate, and washed three times using 200 ⁇ l PBS.
  • About 40 ⁇ l of scint was added to each well and then the plate was allowed to sit at room temperature for 2 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 minute per well using a standard protocol on a Packard top counter.
  • the raw data was fit to a standard 4-parameter equation given below and a value of IC 50 obtained.
  • Representative compounds of the invention were found to have pK b values of greater than 6, and to have IC 50 values of less than about 50 ⁇ m.
  • Tissue (rat heart) muscarininc receptor binding activity of compounds of the invention was tested as follows.
  • Muscarinic receptor enriched membranes were isolated from whole hearts (Pelfreeze Laboratories). Rat heart tissue was typically prepared as follows. 25 ⁇ l of ice cold buffer (20 mM HEPES, 100 mM NaCl/10 mM MgCl 2 at pH 7.5 with “Complete” protease inhibitor cocktail purchased from Boehringer Mannheim was added into an oakridge tube. To the tube was then added 2 g of rat heart (purchased from Harlan). The contents of the tube were then transferred to a wheaton glass cylinder and homogenized using a Polytron homogenizer (setting 22, 15 seconds ⁇ 2), and then transferred back to the oakridge tube, and centrifuged for 10 minutes at 1500 g.
  • a Polytron homogenizer setting 22, 15 seconds ⁇ 2
  • the supernatant was removed and then centrifuged for 20 minutes at 45000 g.
  • the supernatant was removed and the pellet resuspended in 5 mL buffer and transferred to a wheaton glass cylinder.
  • This material was then homogenized using a Potter type glass teflon homogenizer with 7-8 passes.
  • the material was then transferred to an oakridge tube and the total volume was brought up to 25 mL.
  • This material was then centrifuged for 20 minutes at 45000 g, and the pellet re-suspended in 2 mL buffer using 2 passes of a teflon homogenizer, and stored at ⁇ 80° C. until used.
  • a protocol similar to that used for cloned receptor binding was used: Eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 ⁇ M (4 ⁇ the final concentration). To 50 ⁇ l of compound dilution in a 96-well assay plate was added an appropriate amount of rat heart membrane (usually 12.5 ⁇ l of membrane prep in 87.5 ⁇ l of 20 mM HEPES, 100 mM NaCl/10 mM MgCl 2 at pH 7.5). The amount of membrane added depends in general on the results of signal optimization, and ranges from 6.25-12.5 ⁇ l. Last, 50 ⁇ l of 2.12 nM 3H-N-methylscopolamine radioligand was added.
  • the total volume in each well was 200 ⁇ l.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 min., and then washed twice with 200 ⁇ l PBS.
  • the assay plate was incubated for 1 h at room temperature with gentle shaking. The contents of the assay plate were then transferred to the filter plate, and washed three times using 200 ⁇ l PBS.
  • About 40 ⁇ l of scint was added to each well and then the plate was allowed to sit at room temperature for 18 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 min., per well using a standard protocol on the Packard counter. The data was fit to normal isotherms and values for inhibition constants were extracted. Representative compounds of the invention were found to have pK b values of greater than 6, and to have IC 50 values of less than about 50 ⁇ m.
  • Bladder was comprised of both M 2 and M 3 muscarinic receptors. The ratio was typically 4:1 M 2 :M 3 . In order to measure binding of test compounds to one of M 2 or M 3 , the other was blocked with a reversible ligand that binds selectively to that receptor. The following example illustrates the procedure for M 3 bladder binding.
  • Membranes from rat bladder were prepared in a similar fashion to that used to isolate heart membrane above. Eight serial five-fold dilutions were prepared with the compound to be assayed in compound dilution buffer (20 mM HEPES/100 mM NaCl/10 mM MgCl 2 /4 ⁇ M Methoctramine); the highest concentration was typically 4 ⁇ M (4 ⁇ the final concentration). The concentration of methoctramine was sufficient to block >99% of the M2 receptor in bladder, but less than 40% of the M 3 receptor in bladder.
  • rat heart membrane To 50 ⁇ l of compound dilution in a 96-well assay plate was added an appropriate amount of rat heart membrane (usually 25 ⁇ l of membrane prep in 75 ⁇ l of 20 mM HEPES, 100 mM NaCl/10 mM MgCl 2 at pH 7.5). The amount of membrane added depended in general on the results of signal optimization, and ranged from 12.5-25. Last, 50 ⁇ l of 2.12 nM 3H-N-methylscopolamine radioligand in compound dilution buffer was added. The total volume in each well was 200 ⁇ l. The final concentration of methoctramine was 2 ⁇ M.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 mins., and then washed twice with 200 ⁇ l PBS.
  • the assay plate was incubated for 1 hour at room temperature with gentle shaking. The contents of the assay plate was then transferred to the filter plate, and washed three times using 200 ⁇ l PBS.
  • About 40 ⁇ l of scint was added to each well, the plate was allowed to sit at room temperature for 18 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 minute per well using a standard protocol on the Packard counter. The data was fit to normal isotherms and values for inhibition constants were extracted. Representative compounds of the invention were found to have IC 50 values of less than about 500 ⁇ m.
  • test compound The ability of the test compound to inhibit cholinergically stimulated bladder contraction was tested as follows.
  • a cumulative concentration response curve to carbachol (10 ⁇ 8 M to 10 ⁇ 5 M (e.g.) in 3-fold increments) was constructed in each tissue. Tissues were then washed every 5 min., for 30 min., and tension readjusted to 1 g. After additional 30 min., muscarinic antagonist (typically 1 ⁇ 10 ⁇ 7 M) or vehicle was added. Thirty minutes after antagonist or vehicle addition, a cumulative concentration response curve to carbachol (10 ⁇ 8M to 10 ⁇ 3M (e.g.)) was constructed. Data from each concentration response curve was expressed as a percentage of the maximum contraction to carbachol. The EC 50 values were calculated. The concentration-ratios were calculated taking into account any spontaneous shift in the control tissue. For competitive antagonists, the pKb value was calculated using the following equation: pKb - log ⁇ [ antagonist ⁇ ⁇ concentration ] CR - 1
  • Tubing (1.57 mm ID ⁇ 2.08 mm OD) was inserted into the trachea and tied into place with suture thread. The incision was closed leaving the tubing exposed. The tracheotomy was to prevent the animal from asphyxiating on his own saliva following oxotremorine administration.
  • the stomach was shaved and then cleaned with ethanol. A midline sagital incision was made in the skin and muscle layers of the lower stomach.
  • the bladder was exposed and the saline filled cannula (22-gauge needle attached to a pressure transducer with PE 90 tubing) was inserted into the apex of the bladder to the most distal part of the bladder. The bladder was placed back into the peritoneal cavity.
  • the bladder was emptied manually by disconnecting the cannula and allowing the contents to flow out until the bladder was approximately 1 cm in diameter. The incision was closed with suture thread, first the muscle layer, then the skin in order to keep the bladder moist and warm. The exposed portion of the cannula to the skin surface was sutured to hold it in place. After 15 min. oxotremorine (0.3 mg/kg, SC, baseweight) was injected. After 10 min., (or until baseline stabilized) a test compound or a reference standard was injected with a dose equivalent to 0.005-0.01 mg/kg, IV, baseweight of atropine that produced a 30-70% decrease in intraluminal pressure. After 5 min., a high dose of atropine 0.1 mg/kg was injected, i.v., to establish the true 100% inhibition point.
  • oxotremorine 0.3 mg/kg, SC, baseweight
  • the oxotremorine response (zero inhibition) was determined by measuring the mean pressure 1 minute prior to the antagonist injection. Then, to assess antagonist inhibition, mean pressure was measured beginning at 1 minute and ending 2 minutes after antagonist administration. If the pressure had not leveled off after 1 minute, a wait was initiated until it was stable and then a 1-minute sample of the mean was taken. Lastly, to determine the true 100% inhibition point, the mean pressure was measured beginning 1 minutes and ending 2 minutes after the high dose atropine challenge. The percent inhibition by the antagonist can be determined by the ratio of the decrease from the zero to 100% values.
  • the formula is: oxotremorine mean ⁇ treatment mean*100 oxotremorine mean ⁇ atropine mean.
  • the activity of a compound of the invention on other tissues can be determined using screening protocols that are known in the art. For example, an assessment of increased locomotor activity (assay for CNS penetration) can be carried out as described by Sipos M L, et al., (1999) Psychopharmacology 147(3):250-256; an assessment of the effects of a compound on gastrointestinal motility can be carried out as described by Macht D I, and Barba-Gose J (1931) J Am Pharm Assoc 20:558-564; an assessment of the effects of a compound on pupil diameter (mydriasis) can be carried out as described by Parry M, Heathcote B V (1982) Life Sci 31:1465-1471; and an assessment of a compounds effects on urinary bladder in dog can be carried out as described by Newgreen D T, et al. (1996) J Urol 155:600A.
  • Preferred compounds of the invention may display selectivity for one or more tissues over other tissues.
  • compounds of the invention that are useful for treating urinary incontinence may show higher activity in the assay of Example 6 than in the assay of Example 5.
  • Preferred compounds useful for treating urinary incontinence and irritable bowel syndrome have greater antagonist activity at the M 2 receptor than at the M 3 receptor or the other muscarinic receptors.
  • Preferred compounds useful for treating unwanted salivation have greater antagonist activity at the M 3 receptor than at the M 2 receptor or the other muscarinic receptors.

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Abstract

This invention relates to urea compounds that are muscarinic receptor antagonists and agonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS:
  • This application is a continuation-in-part of U.S. patent application Ser. No. 09/456,170, filed Dec. 7, 1999.[0001]
    • BACKGROUND OF THE INVENTION
  • A receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell. [0002]
  • A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool. [0003]
  • The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like). [0004]
  • Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family of five receptor sub-types (M[0005] 1, M2, M3, M4 and M5) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I. et al., Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med., 1989, 321, 1022; Hulme, E. C., et al., Annu. Rev. harmacol.Toxicol. 1990, 30, 633; and Eglen, R. M. and Hegde, S. S., Drug News Perspect. 1997, 10(8), 462-469). For example, the smooth muscle is composed largely of M2 and M3 receptors, cardiac muscle is composed largely of M2 receptors, and salivary glands are largely composed of M3 receptors.
  • It has been established that the muscarinic receptors are involved in diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A., [0006] Invest. Drugs, 1997, 6(10), 1395-141 1; Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137; Graul, A. and Castaner, J., Drugs Future, 1996, 21(11), 1105-1108; and Graul, A., et al., Drugs Future, 1997, 22(7), 733-737).
  • A number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases. For example, oxybutynin is being used for the treatment of urinary urge incontinence and dicyclomine is being used for the treatment of irritable bowel syndrome. However, these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis. [0007]
  • There is currently a need for novel muscarinic receptor antagonists. [0008]
    • SUMMARY OF THE INVENTION
  • The invention is directed to urea derivatives that are muscarinic receptor antagonists and agonists and that are useful in the treatment and prevention of diseases mediated by muscarinic receptors (e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like). [0009]
  • Accordingly, the invention provides a compound of the invention which is a compound of Formula (I): [0010]
  • L1—X—L2
  • wherein: [0011]
  • L[0012] 1 is a group of formula (a):
    Figure US20040054187A1-20040318-C00001
  • wherein: [0013]
  • A is an aryl or a heteroaryl ring; [0014]
  • B″ is —NR[0015] a— wherein Ra is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
  • R[0016] 1 is hydrogen or alkyl;
  • R[0017] 2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii):
    Figure US20040054187A1-20040318-C00002
  • wherein: [0018]
  • - - - is an optional double bond; [0019]
  • n[0020] 1 is an integer of from 1 to 4;
  • n[0021] 2 is an integer of from 1 to 3;
  • V is —CH—, —O—, —S(O)n[0022] 3— (where n3 is an integer of from 0 to 2), or —NR4—(wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
  • “Het” is a heteroaryl ring which optionally attaches (a) to a linker; [0023]
  • R[0024] 3 is hydrogen, alkyl, amino, substituted amino, —ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
  • R[0025] 5 is hydrogen, alkyl, amino, substituted amino, —ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
  • R[0026] 6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
  • K is a bond or an alkylene group; [0027]
  • K″ is a bond, —C(O)—, —S(O)[0028] n4—(where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and
  • B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker; [0029]
  • provided that at least one of the R[0030] 5, R6, R7, R8, “Het”, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
  • X is a linker; [0031]
  • L[0032] 2 is a group selected from a group consisting of:
  • (i) a group of formula (b): [0033]
    Figure US20040054187A1-20040318-C00003
  • wherein: [0034]
  • D″ is alkylene; [0035]
  • D is —NR[0036] 31R32, —N+(R33R34R35) or—OR32 where R31, R33, and R34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R32 and R35 represent a covalent bond attaching (b) to a linker;
  • R[0037] 27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
  • R[0038] 28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
  • R[0039] 29 and R30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or
  • one of R[0040] 27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group;
  • (ii) a group of formula (c): [0041]
    Figure US20040054187A1-20040318-C00004
  • wherein: [0042]
  • n[0043] 11 is an integer of from 1 to 7;
  • n[0044] 12 is 0 to 7;
  • F is —NR[0045] 40—, —O—, —S—, or —CHR41— (wherein R40 and R41 are, independently of each other, hydrogen, alkyl, or substituted alkyl);
  • F″ is a covalent bond, —OR[0046] 43, —NR42R43, or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
  • R[0047] 36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
  • R[0048] 37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and
  • R[0049] 38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R38 and R43 attaches (c) to a linker;
  • R[0050] 39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and
  • (iii) a group of formula (d) or (e): [0051]
    Figure US20040054187A1-20040318-C00005
  • wherein: [0052]
  • R[0053] 46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;
  • R[0054] 47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR50 where R50 is alkyl; or
  • R[0055] 46 and R47 together with the nitrogen atom to which they are attached form heterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more (e.g. 1, 2, 3, or 4) alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R[0056] 48 is a covalent bond that attaches the (d) or the (e) to a linker; and
  • R[0057] 49 is alkyl;
  • or a pharmaceutically acceptable salt; or prodrug thereof. [0058]
  • Preferably X is a group of formula: [0059]
  • —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
  • wherein [0060]
  • m is an integer of from 0 to 20; [0061]
  • X[0062] a at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
  • Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; [0063]
  • Y[0064] a and Yb at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′C(O)—, —NR′ C(O)NR′—, —NR′C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(R″)—NR′—, —NR′—C(R″)═N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)nCR′R″—, —S(O)n—NR′—, —NR′—S(O)n—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic (preferably, at least one of Xa, Ya, Yb or Z is not a covalent bond).
  • The invention also provides a compound of the invention which is a compound of formula (IV): [0065]
    Figure US20040054187A1-20040318-C00006
  • wherein R[0066] 2, K″, A, K, R1, B″, B, X, and L2 have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof. A preferred compound of the invention is a compound of formula (IVa):
    Figure US20040054187A1-20040318-C00007
  • wherein X, and L[0067] 2 have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof.
  • The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof. [0068]
  • The invention also provides synthetic intermediates disclosed herein, as well as synthetic methods useful for preparing such intermediates, and synthetic methods useful for preparing compounds of the invention or salts thereof. [0069]
  • The invention also provides a method of treating diseases mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof. [0070]
  • The invention also provides a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for use in medical therapy, as well as the use of a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a disease mediated by a muscarinic receptor in a mammal. [0071]
  • Applicant has discovered that urea compounds of the present invention are metabolically more stable than compounds lacking such a urea functionality. Accordingly, compounds of the present invention have longer metabolic half-lives and/or longer duration of action in vivo, which can reduce the dose required for administration or can reduce the likelihood of the generation of unwanted metabolites. [0072]
    • DETAILED DESCRIPTION OF THE INVENTION
  • The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings. [0073]
  • The term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like. [0074]
  • The term “substituted alkyl” refers to an alkyl group as defined above wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as —O—, —S(O)n— (where n is 0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO[0075] 2-alkyl, —SO2-aryl, —SO2-heteroaryl, and -NRaRb, wherein Ra and Rb may be the same or different and and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminoprppyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like.
  • The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (—CH[0076] 2—), ethylene (—CH2CH2—), the propylene isomers (e.g., —CH2CH2CH2— and —CH(CH3)CH2—) and the like.
  • The term “substituted alkylene” refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0077] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures.
  • The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl” refers to the groups R[0078] aNHRb— where Ra is alkyl group as defined above and Rb is alkylene, alkenylene or alkynylene group as defined above. Such groups are exemplified by 3-methylaminobutyl, 4-ethylamino-1,1-dimethylbutyn-1-yl, 4-ethylaminobutyn-1-yl, and the like.
  • The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like. [0079]
  • The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—, cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-O— and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. [0080]
  • The term “substituted alkoxy” refers to the groups substituted alkyl-O—, substituted alkenyl-O—, substituted cycloalkyl-O—, substituted cycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein. [0081]
  • The term “haloalkoxy” refers to the groups alkyl-O— wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like. [0082]
  • The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (—CH[0083] 2OCH3), ethylenemethoxy (—CH2CH2OCH3), n-propylene-iso-propoxy (—CH2CH2CH2OCH(CH3)2), methylene-t-butoxy (—CH2—O—C(CH3)3), and the like.
  • The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (—CH[0084] 2SCH3), ethylenethiomethoxy (—CH2CH2SCH3), n-propylene-iso-thiopropoxy (—CH2CH2CH2SCH(CH3)2), methylene-t-thiobutoxy (—CH2SC(CH3)3), and the like.
  • The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH[0085] 2), n-propenyl (—CH2CH═CH2), iso-propenyl (—C(CH3)═CH2), and the like.
  • The term “substituted alkenyl” refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0086] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl.
  • The term “alkenylene” refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH[0087] 2CH═CH— or —C(CH3)═CH—), and the like.
  • The term “substituted alkenylene” refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, amninoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0088] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl. Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
  • The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH[0089] 2C≡CH), and the like.
  • The term “substituted alkynyl” refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0090] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl, and —SO2-heteroaryl.
  • The term “alkynylene” refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (—CE≡C—), propargylene (—CH[0091] 2C≡C—), and the like.
  • The term “substituted alkynylene” refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, arninoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0092] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl.
  • The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic are as defined herein. [0093]
  • The term “acylamino” or “aminocarbonyl” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein. [0094]
  • The term “aminoacyl” refers to the group —NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein. [0095]
  • The term “aminoacyloxy” or “alkoxycarbonylamino” refers to the group —NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein. [0096]
  • The term “acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein. [0097]
  • The term “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0098] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • The term “aryloxy” refers to the group aryl-O— wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above. [0099]
  • The term “arylene ” refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like. [0100]
  • The term “amino” refers to the group —NH[0101] 2.
  • The term “substituted amino” refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic provided that both R's are not hydrogen. [0102]
  • The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups “—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”, “—C(O)O-substituted cycloalkyl”, “—C(O)O-alkenyl”, “—C(O)O-substituted alkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein. [0103]
  • The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. [0104]
  • The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0105] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl.
  • The term “cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like. [0106]
  • The term “substituted cycloalkenyl” refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0107] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl.
  • The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [0108]
  • The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0109] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. Such heteroaralkyl groups are exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and the like. [0110]
  • The term “heteroaryloxy” refers to the group heteroaryl-O—. [0111]
  • The term “heteroarylene” refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like. [0112]
  • The term “heterocycle” or “heterocyclic” or refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO[0113] 2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
  • Examples of nitrogen heteroaryls and heterocycles include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofuranyl, tetrahydrothiophene, and the like as well as N-alkoxy-nitrogen containing heterocycles. [0114]
  • The term “heterocyclooxy” refers to the group heterocyclic-O—. [0115]
  • The term “thioheterocyclooxy” refers to the group heterocyclic-S—. [0116]
  • The term “heterocyclene” refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morpholino and the like. [0117]
  • “Heteroarylamino” means a 5 membered aromatic ring wherein one or two ring atoms are N, the remaining ring atoms being C. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, —OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or —S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, imidazole, pyrazole, benzimidazole and benzpyrazole. [0118]
  • “Heterocycloamino” means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, indolino, or thiomorpholino. The term heterocycloamino also includes, quinuclidine, 1 -azabicyclo[2.2.1]heptyl, 1-azabicyclo[3.2.1]octyl and the derivatives thereof. [0119]
  • The term “oxyacylamino ” or “aminocarbonyloxy” refers to the group —OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein. [0120]
  • The term “spiro-attached cycloalkyl group ” refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings. [0121]
  • The term “thiol” refers to the group —SH. [0122]
  • The term “thioalkoxy” or “alkylthio” refers to the group —S-alkyl. [0123]
  • The term “substituted thioalkoxy” refers to the group —S-substituted alkyl. [0124]
  • The term “thioaryloxy” refers to the group aryl-S— wherein the aryl group is as defined above including optionally substituted aryl groups also defined above. [0125]
  • The term “thioheteroaryloxy” refers to the group heteroaryl-S— wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above. [0126]
  • As to any of the above groups which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds. [0127]
  • Unless specified otherwise, all ranges referred to herein include the stated end-point values. [0128]
  • The term “pharmaceutically-acceptable salt” refers to salts which retain biological effectiveness and are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. [0129]
  • Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like. [0130]
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. [0131]
  • The term “pharmaceutically-acceptable cation ” refers to the cation of a pharmaceutically-acceptable salt. [0132]
  • The term “protecting group” or “blocking group” refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product. Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product. [0133]
  • The term “optional” or “optionally” means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. [0134]
  • The term “inert organic solvent” or “inert organic solvent” means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert solvents. [0135]
  • The term “treatment” refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes: [0136]
  • (i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition; [0137]
  • (ii) inhibiting the pathologic condition, i.e., arresting its development; [0138]
  • (iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or [0139]
  • (iv) relieving the conditions mediated by the pathologic condition. [0140]
  • The term “pathologic condition which is modulated by treatment with a ligand” covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the muscarinic receptors in general, and those disease states which have been found to be usefully treated by a compound of the invention. Such disease states include, by way of example only, the treatment of a mammal afflicted with chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like. [0141]
  • The term “therapeutically effective amount” refers to that amount of a compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. [0142]
  • The term “linker”, identified by the symbol ‘X’ refers to a group or groups that covalently attaches L[0143] 1 and L2. Additionally, the linker can be either a chiral or achiral molecule. The term “linker” does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the compounds of this invention can be attached to a solid support if desired. For example, such attachment to solid supports can be made for use in separation and purification processes and similar applications.
  • “Pro-drugs” means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (D) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like. [0144]
  • While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) may be preferred. Specific and preferred values listed herein for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents [0145]
  • A preferred value for A is phenyl or pyridine [0146]
  • A preferred value for R[0147] 1 is hydrogen methyl, or ethyl.
  • Another preferred value for R[0148] 1 is hydrogen.
  • A preferred value for R[0149] 2 is pyrrolyl, pyridinyl, or imidazolyl.
  • Another preferred value for R[0150] 2 is phenyl.
  • A preferred value for V is —CH— or —NR[0151] 4— (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl).
  • A preferred value for R[0152] 3 is hydrogen or alkyl
  • A preferred value for R[0153] 5 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker
  • Another preferred value for R[0154] 5 is hydrogen, methyl, phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino.
  • A preferred value for R[0155] 6, R7, and R8 independent of each other is hydrogen, alkyl, nitro, hydroxy, or amino.
  • A preferred value for K is alkylene having from 1 to 10 carbon atoms. [0156]
  • A preferred value for K is alkylene having from 1 to 5 carbon atoms. [0157]
  • A preferred value for K is a bond or a methylene group. [0158]
  • A preferred value for K″ is a bond. [0159]
  • A preferred value for R[0160] a is hydrogen.
  • A preferred value for B is a heterocycloamino group which attaches (a) to a linker. [0161]
  • Another preferred value for B is a formula selected from a group consisting of formula (j), formula (k), and formula (l): [0162]
    Figure US20040054187A1-20040318-C00008
  • wherein: [0163]
  • n[0164] 13 and n14 are, independently of each other, an integer of from 0 to 4 provided that n13+n14 is an integer of from 3 to 5;
  • n[0165] 15 and n17 are, independently of each other, an integer of from 0 to 4 provided that n15+n17 is an integer of from 3 to 5;
  • n[0166] 16 is an integer of from 0 to 3 provided that n15+n16 is an integer of from 3 to 5;
  • n[0167] 18, n19 and n20 are, independently of each other, an integer of from 0 to 3 provided that n18+n19+n20 is 2 or 3;
  • n[0168] 21 is an integer of from 1 to 3;
  • W[0169] a and Wc are, independently of each other:
    Figure US20040054187A1-20040318-C00009
  • where: [0170]
  • n[0171] 22 is 0 or 1;
  • R[0172] 53 and R54 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl or a covalent bond attaching (a) to a linker;
  • R[0173] 55 is alkyl, alkenyl or alkynyl; and
  • W[0174] b is —N(O)n23 or —N+—R56 where n23 is 0 or 1, and R56 is alkyl, alkenyl, alkynyl, or aralkyl, or a covalent bond attaching (a) to a linker;
  • provided that a carbon other than a bridge head carbon is bonded to B″. [0175]
  • Another preferred value for B is a ring represented by the following general formulae: [0176]
    Figure US20040054187A1-20040318-C00010
  • wherein a carbon atom other than a bridge head carbon is bound to B″; and W[0177] c is as defined above.
  • A more preferred value for B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker. [0178]
  • Another more preferred value for B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker. [0179]
  • Another more preferred value for B is piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker. [0180]
  • Another more preferred value for B is quinuclidine, 1-azabicyclo[2.2.1]-heptyl, or 1-azabicyclo[3.2.1]octyl attaching (a) to a linker, wherein a carbon other than a bridge head carbon is bound to B″. [0181]
  • A preferred value for D″ is —(CH[0182] 2)n43— where n43 is an integer of from 1-10, preferably 2-8, more preferably 2-4. Another preferred value for n43 is an integer of from 3-10.
  • A preferred value for D is —NR[0183] 31R32 or —N+(R33R34R35)M− where R31, R33, and R34 are, independently of each other, hydrogen or methyl, and R32 and R35 represent a covalent bond attaching (b) to a linker. More preferably R31, R33, and R34 methyl, and R32 and R35 represent a covalent bond attaching (b) to a linker.
  • A preferred value for R[0184] 27 is hydrogen.
  • A preferred value for R[0185] 28 is hydrogen.
  • A preferred value for R[0186] 29 and R30 independently is hydrogen; or one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group.
  • A preferred value for n[0187] 11 is 1.
  • A preferred value for n[0188] 12 is 6.
  • A preferred value for F is —O—. [0189]
  • A preferred value for F″ is a covalent bond, —OR[0190] 43, —NR42R43 wherein R42 is hydrogen or alkyl, or —N+(R43R44R45) wherein R44 and R45 are alkyl, and R43 is a covalent bond attaching (c) to a linker.
  • A preferred value for F″ is —O—, —NH—, N(CH[0191] 3)— or —N(CH3)2—
  • A more preferred value for F″ is —NH—, N(CH[0192] 3)— or —N(CH3)2— wherein the nitrogen atom attaches (c) to a linker.
  • A preferred value for R[0193] 36 is hydrogen.
  • Preferably R[0194] 37 is ortho to the —(CHR38)— group and is hydrogen or alkoxy. More preferably R37 is ortho to the —(CHR38)— group and is methoxy.
  • Preferably is R[0195] 38 is hydrogen.
  • Preferably R[0196] 39 is hydrogen.
  • Preferably L[0197] 2 is a group of formula (d) wherein: R46 is alkyl or substituted alkyl; R47 is alkyl, substituted alkyl, or heterocycle; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle.
  • Preferably, L[0198] 2 is a group of formula A1-A241 as shown in the following table. L2 is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L2.
    No. L2
    A1
    Figure US20040054187A1-20040318-C00011
    A2
    Figure US20040054187A1-20040318-C00012
    A3
    Figure US20040054187A1-20040318-C00013
    A4
    Figure US20040054187A1-20040318-C00014
    A5
    Figure US20040054187A1-20040318-C00015
    A6
    Figure US20040054187A1-20040318-C00016
    A7
    Figure US20040054187A1-20040318-C00017
    A8
    Figure US20040054187A1-20040318-C00018
    A9
    Figure US20040054187A1-20040318-C00019
    A10
    Figure US20040054187A1-20040318-C00020
    A11
    Figure US20040054187A1-20040318-C00021
    A12
    Figure US20040054187A1-20040318-C00022
    A13
    Figure US20040054187A1-20040318-C00023
    A14
    Figure US20040054187A1-20040318-C00024
    A15
    Figure US20040054187A1-20040318-C00025
    A16
    Figure US20040054187A1-20040318-C00026
    A17
    Figure US20040054187A1-20040318-C00027
    A18
    Figure US20040054187A1-20040318-C00028
    A19
    Figure US20040054187A1-20040318-C00029
    A20
    Figure US20040054187A1-20040318-C00030
    A21
    Figure US20040054187A1-20040318-C00031
    A22
    Figure US20040054187A1-20040318-C00032
    A23
    Figure US20040054187A1-20040318-C00033
    A24
    Figure US20040054187A1-20040318-C00034
    A25
    Figure US20040054187A1-20040318-C00035
    A26
    Figure US20040054187A1-20040318-C00036
    A27
    Figure US20040054187A1-20040318-C00037
    A28
    Figure US20040054187A1-20040318-C00038
    A29
    Figure US20040054187A1-20040318-C00039
    A30
    Figure US20040054187A1-20040318-C00040
    A31
    Figure US20040054187A1-20040318-C00041
    A32
    Figure US20040054187A1-20040318-C00042
    A33
    Figure US20040054187A1-20040318-C00043
    A34
    Figure US20040054187A1-20040318-C00044
    A35
    Figure US20040054187A1-20040318-C00045
    A36
    Figure US20040054187A1-20040318-C00046
    A37
    Figure US20040054187A1-20040318-C00047
    A38
    Figure US20040054187A1-20040318-C00048
    A39
    Figure US20040054187A1-20040318-C00049
    A40
    Figure US20040054187A1-20040318-C00050
    A41
    Figure US20040054187A1-20040318-C00051
    A42
    Figure US20040054187A1-20040318-C00052
    A43
    Figure US20040054187A1-20040318-C00053
    A44
    Figure US20040054187A1-20040318-C00054
    A45
    Figure US20040054187A1-20040318-C00055
    A46
    Figure US20040054187A1-20040318-C00056
    A47
    Figure US20040054187A1-20040318-C00057
    A48
    Figure US20040054187A1-20040318-C00058
    A49
    Figure US20040054187A1-20040318-C00059
    A50
    Figure US20040054187A1-20040318-C00060
    A51
    Figure US20040054187A1-20040318-C00061
    A52
    Figure US20040054187A1-20040318-C00062
    A53
    Figure US20040054187A1-20040318-C00063
    A54
    Figure US20040054187A1-20040318-C00064
    A55
    Figure US20040054187A1-20040318-C00065
    A56
    Figure US20040054187A1-20040318-C00066
    A57
    Figure US20040054187A1-20040318-C00067
    A58
    Figure US20040054187A1-20040318-C00068
    A59
    Figure US20040054187A1-20040318-C00069
    A60
    Figure US20040054187A1-20040318-C00070
    A61
    Figure US20040054187A1-20040318-C00071
    A62
    Figure US20040054187A1-20040318-C00072
    A63
    Figure US20040054187A1-20040318-C00073
    A64
    Figure US20040054187A1-20040318-C00074
    A65
    Figure US20040054187A1-20040318-C00075
    A66
    Figure US20040054187A1-20040318-C00076
    A67
    Figure US20040054187A1-20040318-C00077
    A68
    Figure US20040054187A1-20040318-C00078
    A69
    Figure US20040054187A1-20040318-C00079
    A70
    Figure US20040054187A1-20040318-C00080
    A71
    Figure US20040054187A1-20040318-C00081
    A72
    Figure US20040054187A1-20040318-C00082
    A73
    Figure US20040054187A1-20040318-C00083
    A74
    Figure US20040054187A1-20040318-C00084
    A75
    Figure US20040054187A1-20040318-C00085
    A76
    Figure US20040054187A1-20040318-C00086
    A77
    Figure US20040054187A1-20040318-C00087
    A78
    Figure US20040054187A1-20040318-C00088
    A79
    Figure US20040054187A1-20040318-C00089
    A80
    Figure US20040054187A1-20040318-C00090
    A81
    Figure US20040054187A1-20040318-C00091
    A82
    Figure US20040054187A1-20040318-C00092
    A83
    Figure US20040054187A1-20040318-C00093
    A84
    Figure US20040054187A1-20040318-C00094
    A85
    Figure US20040054187A1-20040318-C00095
    A86
    Figure US20040054187A1-20040318-C00096
    A87
    Figure US20040054187A1-20040318-C00097
    A88
    Figure US20040054187A1-20040318-C00098
    A89
    Figure US20040054187A1-20040318-C00099
    A90
    Figure US20040054187A1-20040318-C00100
    A91
    Figure US20040054187A1-20040318-C00101
    A92
    Figure US20040054187A1-20040318-C00102
    A93
    Figure US20040054187A1-20040318-C00103
    A94
    Figure US20040054187A1-20040318-C00104
    A95
    Figure US20040054187A1-20040318-C00105
    A96
    Figure US20040054187A1-20040318-C00106
    A97
    Figure US20040054187A1-20040318-C00107
    A98
    Figure US20040054187A1-20040318-C00108
    A99
    Figure US20040054187A1-20040318-C00109
    A100
    Figure US20040054187A1-20040318-C00110
    A101
    Figure US20040054187A1-20040318-C00111
    A102
    Figure US20040054187A1-20040318-C00112
    A103
    Figure US20040054187A1-20040318-C00113
    A104
    Figure US20040054187A1-20040318-C00114
    A105
    Figure US20040054187A1-20040318-C00115
    A106
    Figure US20040054187A1-20040318-C00116
    A107
    Figure US20040054187A1-20040318-C00117
    A108
    Figure US20040054187A1-20040318-C00118
    A109
    Figure US20040054187A1-20040318-C00119
    A110
    Figure US20040054187A1-20040318-C00120
    A111
    Figure US20040054187A1-20040318-C00121
    A112
    Figure US20040054187A1-20040318-C00122
    A113
    Figure US20040054187A1-20040318-C00123
    A114
    Figure US20040054187A1-20040318-C00124
    A115
    Figure US20040054187A1-20040318-C00125
    A116
    Figure US20040054187A1-20040318-C00126
    A117
    Figure US20040054187A1-20040318-C00127
    A118
    Figure US20040054187A1-20040318-C00128
    A119
    Figure US20040054187A1-20040318-C00129
    A120
    Figure US20040054187A1-20040318-C00130
    A121
    Figure US20040054187A1-20040318-C00131
    A122
    Figure US20040054187A1-20040318-C00132
    A123
    Figure US20040054187A1-20040318-C00133
    A124
    Figure US20040054187A1-20040318-C00134
    A125
    Figure US20040054187A1-20040318-C00135
    A126
    Figure US20040054187A1-20040318-C00136
    A127
    Figure US20040054187A1-20040318-C00137
    A128
    Figure US20040054187A1-20040318-C00138
    A129
    Figure US20040054187A1-20040318-C00139
    A130
    Figure US20040054187A1-20040318-C00140
    A131
    Figure US20040054187A1-20040318-C00141
    A132
    Figure US20040054187A1-20040318-C00142
    A133
    Figure US20040054187A1-20040318-C00143
    A134
    Figure US20040054187A1-20040318-C00144
    A135
    Figure US20040054187A1-20040318-C00145
    A136
    Figure US20040054187A1-20040318-C00146
    A137
    Figure US20040054187A1-20040318-C00147
    A138
    Figure US20040054187A1-20040318-C00148
    A139
    Figure US20040054187A1-20040318-C00149
    A140
    Figure US20040054187A1-20040318-C00150
    A141
    Figure US20040054187A1-20040318-C00151
    A142
    Figure US20040054187A1-20040318-C00152
    A143
    Figure US20040054187A1-20040318-C00153
    A144
    Figure US20040054187A1-20040318-C00154
    A145
    Figure US20040054187A1-20040318-C00155
    A146
    Figure US20040054187A1-20040318-C00156
    A147
    Figure US20040054187A1-20040318-C00157
    A148
    Figure US20040054187A1-20040318-C00158
    A149
    Figure US20040054187A1-20040318-C00159
    A150
    Figure US20040054187A1-20040318-C00160
    A151
    Figure US20040054187A1-20040318-C00161
    A152
    Figure US20040054187A1-20040318-C00162
    A153
    Figure US20040054187A1-20040318-C00163
    A154
    Figure US20040054187A1-20040318-C00164
    A155
    Figure US20040054187A1-20040318-C00165
    A156
    Figure US20040054187A1-20040318-C00166
    A157
    Figure US20040054187A1-20040318-C00167
    A158
    Figure US20040054187A1-20040318-C00168
    A159
    Figure US20040054187A1-20040318-C00169
    A160
    Figure US20040054187A1-20040318-C00170
    A161
    Figure US20040054187A1-20040318-C00171
    A162
    Figure US20040054187A1-20040318-C00172
    A163
    Figure US20040054187A1-20040318-C00173
    A164
    Figure US20040054187A1-20040318-C00174
    A165
    Figure US20040054187A1-20040318-C00175
    A166
    Figure US20040054187A1-20040318-C00176
    A167
    Figure US20040054187A1-20040318-C00177
    A168
    Figure US20040054187A1-20040318-C00178
    A169
    Figure US20040054187A1-20040318-C00179
    A170
    Figure US20040054187A1-20040318-C00180
    A171
    Figure US20040054187A1-20040318-C00181
    A172
    Figure US20040054187A1-20040318-C00182
    A173
    Figure US20040054187A1-20040318-C00183
    A174
    Figure US20040054187A1-20040318-C00184
    A175
    Figure US20040054187A1-20040318-C00185
    A176
    Figure US20040054187A1-20040318-C00186
    A177
    Figure US20040054187A1-20040318-C00187
    A178
    Figure US20040054187A1-20040318-C00188
    A179
    Figure US20040054187A1-20040318-C00189
    A180
    Figure US20040054187A1-20040318-C00190
    A181
    Figure US20040054187A1-20040318-C00191
    A182
    Figure US20040054187A1-20040318-C00192
    A183
    Figure US20040054187A1-20040318-C00193
    A184
    Figure US20040054187A1-20040318-C00194
    A185
    Figure US20040054187A1-20040318-C00195
    A186
    Figure US20040054187A1-20040318-C00196
    A187
    Figure US20040054187A1-20040318-C00197
    A188
    Figure US20040054187A1-20040318-C00198
    A189
    Figure US20040054187A1-20040318-C00199
    A190
    Figure US20040054187A1-20040318-C00200
    A191
    Figure US20040054187A1-20040318-C00201
    A192
    Figure US20040054187A1-20040318-C00202
    A193
    Figure US20040054187A1-20040318-C00203
    A194
    Figure US20040054187A1-20040318-C00204
    A195
    Figure US20040054187A1-20040318-C00205
    A196
    Figure US20040054187A1-20040318-C00206
    A197
    Figure US20040054187A1-20040318-C00207
    A198
    Figure US20040054187A1-20040318-C00208
    A199
    Figure US20040054187A1-20040318-C00209
    A200
    Figure US20040054187A1-20040318-C00210
    A201
    Figure US20040054187A1-20040318-C00211
    A202
    Figure US20040054187A1-20040318-C00212
    A203
    Figure US20040054187A1-20040318-C00213
    A204
    Figure US20040054187A1-20040318-C00214
    A205
    Figure US20040054187A1-20040318-C00215
    A206
    Figure US20040054187A1-20040318-C00216
    A207
    Figure US20040054187A1-20040318-C00217
    A208
    Figure US20040054187A1-20040318-C00218
    A209
    Figure US20040054187A1-20040318-C00219
    A210
    Figure US20040054187A1-20040318-C00220
    A211
    Figure US20040054187A1-20040318-C00221
    A212
    Figure US20040054187A1-20040318-C00222
    A213
    Figure US20040054187A1-20040318-C00223
    A214
    Figure US20040054187A1-20040318-C00224
    A215
    Figure US20040054187A1-20040318-C00225
    A216
    Figure US20040054187A1-20040318-C00226
    A217
    Figure US20040054187A1-20040318-C00227
    A218
    Figure US20040054187A1-20040318-C00228
    A219
    Figure US20040054187A1-20040318-C00229
    A220
    Figure US20040054187A1-20040318-C00230
    A221
    Figure US20040054187A1-20040318-C00231
    A222
    Figure US20040054187A1-20040318-C00232
    A223
    Figure US20040054187A1-20040318-C00233
    A224
    Figure US20040054187A1-20040318-C00234
    A225
    Figure US20040054187A1-20040318-C00235
    A226
    Figure US20040054187A1-20040318-C00236
    A227
    Figure US20040054187A1-20040318-C00237
    A228
    Figure US20040054187A1-20040318-C00238
    A229
    Figure US20040054187A1-20040318-C00239
    A230
    Figure US20040054187A1-20040318-C00240
    A231
    Figure US20040054187A1-20040318-C00241
    A232
    Figure US20040054187A1-20040318-C00242
    A233
    Figure US20040054187A1-20040318-C00243
    A234
    Figure US20040054187A1-20040318-C00244
    A235
    Figure US20040054187A1-20040318-C00245
    A236
    Figure US20040054187A1-20040318-C00246
    A237
    Figure US20040054187A1-20040318-C00247
    A238
    Figure US20040054187A1-20040318-C00248
    A239
    Figure US20040054187A1-20040318-C00249
    A240
    Figure US20040054187A1-20040318-C00250
    A241
    Figure US20040054187A1-20040318-C00251
  • Preferably, L[0199] 2 can also be a group of formula A301-A439 as shown in the following table. L2 is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L2.
    A301
    Figure US20040054187A1-20040318-C00252
    A302
    Figure US20040054187A1-20040318-C00253
    A303
    Figure US20040054187A1-20040318-C00254
    A304
    Figure US20040054187A1-20040318-C00255
    A305
    Figure US20040054187A1-20040318-C00256
    A306
    Figure US20040054187A1-20040318-C00257
    A307
    Figure US20040054187A1-20040318-C00258
    A308
    Figure US20040054187A1-20040318-C00259
    A309
    Figure US20040054187A1-20040318-C00260
    A310
    Figure US20040054187A1-20040318-C00261
    A311
    Figure US20040054187A1-20040318-C00262
    A312
    Figure US20040054187A1-20040318-C00263
    A313
    Figure US20040054187A1-20040318-C00264
    A314
    Figure US20040054187A1-20040318-C00265
    A315
    Figure US20040054187A1-20040318-C00266
    A316
    Figure US20040054187A1-20040318-C00267
    A317
    Figure US20040054187A1-20040318-C00268
    A318
    Figure US20040054187A1-20040318-C00269
    A319
    Figure US20040054187A1-20040318-C00270
    A320
    Figure US20040054187A1-20040318-C00271
    A321
    Figure US20040054187A1-20040318-C00272
    A322
    Figure US20040054187A1-20040318-C00273
    A323
    Figure US20040054187A1-20040318-C00274
    A324
    Figure US20040054187A1-20040318-C00275
    A325
    Figure US20040054187A1-20040318-C00276
    A326
    Figure US20040054187A1-20040318-C00277
    A327
    Figure US20040054187A1-20040318-C00278
    A328
    Figure US20040054187A1-20040318-C00279
    A329
    Figure US20040054187A1-20040318-C00280
    A330
    Figure US20040054187A1-20040318-C00281
    A331
    Figure US20040054187A1-20040318-C00282
    A332
    Figure US20040054187A1-20040318-C00283
    A333
    Figure US20040054187A1-20040318-C00284
    A334
    Figure US20040054187A1-20040318-C00285
    A335
    Figure US20040054187A1-20040318-C00286
    A336
    Figure US20040054187A1-20040318-C00287
    A337
    Figure US20040054187A1-20040318-C00288
    A338
    Figure US20040054187A1-20040318-C00289
    A339
    Figure US20040054187A1-20040318-C00290
    A340
    Figure US20040054187A1-20040318-C00291
    A341
    Figure US20040054187A1-20040318-C00292
    A342
    Figure US20040054187A1-20040318-C00293
    A343
    Figure US20040054187A1-20040318-C00294
    A344
    Figure US20040054187A1-20040318-C00295
    A345
    Figure US20040054187A1-20040318-C00296
    A346
    Figure US20040054187A1-20040318-C00297
    A347
    Figure US20040054187A1-20040318-C00298
    A348
    Figure US20040054187A1-20040318-C00299
    A349
    Figure US20040054187A1-20040318-C00300
    A350
    Figure US20040054187A1-20040318-C00301
    A351
    Figure US20040054187A1-20040318-C00302
    A352
    Figure US20040054187A1-20040318-C00303
    A353
    Figure US20040054187A1-20040318-C00304
    A354
    Figure US20040054187A1-20040318-C00305
    A355
    Figure US20040054187A1-20040318-C00306
    A356
    Figure US20040054187A1-20040318-C00307
    A357
    Figure US20040054187A1-20040318-C00308
    A358
    Figure US20040054187A1-20040318-C00309
    A359
    Figure US20040054187A1-20040318-C00310
    A360
    Figure US20040054187A1-20040318-C00311
    A361
    Figure US20040054187A1-20040318-C00312
    A362
    Figure US20040054187A1-20040318-C00313
    A363
    Figure US20040054187A1-20040318-C00314
    A364
    Figure US20040054187A1-20040318-C00315
    A365
    Figure US20040054187A1-20040318-C00316
    A366
    Figure US20040054187A1-20040318-C00317
    A367
    Figure US20040054187A1-20040318-C00318
    A368
    Figure US20040054187A1-20040318-C00319
    A369
    Figure US20040054187A1-20040318-C00320
    A370
    Figure US20040054187A1-20040318-C00321
    A371
    Figure US20040054187A1-20040318-C00322
    A372
    Figure US20040054187A1-20040318-C00323
    A373
    Figure US20040054187A1-20040318-C00324
    A374
    Figure US20040054187A1-20040318-C00325
    A375
    Figure US20040054187A1-20040318-C00326
    A376
    Figure US20040054187A1-20040318-C00327
    A377
    Figure US20040054187A1-20040318-C00328
    A378
    Figure US20040054187A1-20040318-C00329
    A379
    Figure US20040054187A1-20040318-C00330
    A380
    Figure US20040054187A1-20040318-C00331
    A381
    Figure US20040054187A1-20040318-C00332
    A382
    Figure US20040054187A1-20040318-C00333
    A383
    Figure US20040054187A1-20040318-C00334
    A384
    Figure US20040054187A1-20040318-C00335
    A385
    Figure US20040054187A1-20040318-C00336
    A386
    Figure US20040054187A1-20040318-C00337
    A387
    Figure US20040054187A1-20040318-C00338
    A388
    Figure US20040054187A1-20040318-C00339
    A389
    Figure US20040054187A1-20040318-C00340
    A390
    Figure US20040054187A1-20040318-C00341
    A391
    Figure US20040054187A1-20040318-C00342
    A393
    Figure US20040054187A1-20040318-C00343
    A394
    Figure US20040054187A1-20040318-C00344
    A395
    Figure US20040054187A1-20040318-C00345
    A396
    Figure US20040054187A1-20040318-C00346
    A397
    Figure US20040054187A1-20040318-C00347
    A398
    Figure US20040054187A1-20040318-C00348
    A399
    Figure US20040054187A1-20040318-C00349
    A400
    Figure US20040054187A1-20040318-C00350
    A401
    Figure US20040054187A1-20040318-C00351
    A402
    Figure US20040054187A1-20040318-C00352
    A403
    Figure US20040054187A1-20040318-C00353
    A404
    Figure US20040054187A1-20040318-C00354
    A405
    Figure US20040054187A1-20040318-C00355
    A406
    Figure US20040054187A1-20040318-C00356
    A407
    Figure US20040054187A1-20040318-C00357
    A408
    Figure US20040054187A1-20040318-C00358
    A409
    Figure US20040054187A1-20040318-C00359
    A410
    Figure US20040054187A1-20040318-C00360
    A411
    Figure US20040054187A1-20040318-C00361
    A412
    Figure US20040054187A1-20040318-C00362
    A413
    Figure US20040054187A1-20040318-C00363
    A414
    Figure US20040054187A1-20040318-C00364
    A415
    Figure US20040054187A1-20040318-C00365
    A416
    Figure US20040054187A1-20040318-C00366
    A417
    Figure US20040054187A1-20040318-C00367
    A418
    Figure US20040054187A1-20040318-C00368
    A419
    Figure US20040054187A1-20040318-C00369
    A420
    Figure US20040054187A1-20040318-C00370
    A421
    Figure US20040054187A1-20040318-C00371
    A422
    Figure US20040054187A1-20040318-C00372
    A423
    Figure US20040054187A1-20040318-C00373
    A424
    Figure US20040054187A1-20040318-C00374
    A425
    Figure US20040054187A1-20040318-C00375
    A426
    Figure US20040054187A1-20040318-C00376
    A427
    Figure US20040054187A1-20040318-C00377
    A428
    Figure US20040054187A1-20040318-C00378
    A429
    Figure US20040054187A1-20040318-C00379
    A430
    Figure US20040054187A1-20040318-C00380
    A431
    Figure US20040054187A1-20040318-C00381
    A432
    Figure US20040054187A1-20040318-C00382
    A433
    Figure US20040054187A1-20040318-C00383
    A434
    Figure US20040054187A1-20040318-C00384
    A435
    Figure US20040054187A1-20040318-C00385
    A436
    Figure US20040054187A1-20040318-C00386
    A437
    Figure US20040054187A1-20040318-C00387
    A438
    Figure US20040054187A1-20040318-C00388
    A439
    Figure US20040054187A1-20040318-C00389
  • Preferably, L[0200] 2 can also be a group of formula A501-A523 as shown in the following table. L2 is preferably linked to X through a non-aromatic nitrogen atom of L2.
    No. L2
    A501
    Figure US20040054187A1-20040318-C00390
    A502
    Figure US20040054187A1-20040318-C00391
    A503
    Figure US20040054187A1-20040318-C00392
    A504
    Figure US20040054187A1-20040318-C00393
    A505
    Figure US20040054187A1-20040318-C00394
    A506
    Figure US20040054187A1-20040318-C00395
    A507
    Figure US20040054187A1-20040318-C00396
    A508
    Figure US20040054187A1-20040318-C00397
    A509
    Figure US20040054187A1-20040318-C00398
    A510
    Figure US20040054187A1-20040318-C00399
    A511
    Figure US20040054187A1-20040318-C00400
    A512
    Figure US20040054187A1-20040318-C00401
    A513
    Figure US20040054187A1-20040318-C00402
    A514
    Figure US20040054187A1-20040318-C00403
    A515
    Figure US20040054187A1-20040318-C00404
    A516
    Figure US20040054187A1-20040318-C00405
    A517
    Figure US20040054187A1-20040318-C00406
    A518
    Figure US20040054187A1-20040318-C00407
    A519
    Figure US20040054187A1-20040318-C00408
    A520
    Figure US20040054187A1-20040318-C00409
    A521
    Figure US20040054187A1-20040318-C00410
    A522
    Figure US20040054187A1-20040318-C00411
    A523
    Figure US20040054187A1-20040318-C00412
    A524
    Figure US20040054187A1-20040318-C00413
    A525
    Figure US20040054187A1-20040318-C00414
    A526
    Figure US20040054187A1-20040318-C00415
    A527
    Figure US20040054187A1-20040318-C00416
    A528
    Figure US20040054187A1-20040318-C00417
    A529
    Figure US20040054187A1-20040318-C00418
    A530
    Figure US20040054187A1-20040318-C00419
    A531
    Figure US20040054187A1-20040318-C00420
    A532
    Figure US20040054187A1-20040318-C00421
    A533
    Figure US20040054187A1-20040318-C00422
    A534
    Figure US20040054187A1-20040318-C00423
    A535
    Figure US20040054187A1-20040318-C00424
    A536
    Figure US20040054187A1-20040318-C00425
    A537
    Figure US20040054187A1-20040318-C00426
    A538
    Figure US20040054187A1-20040318-C00427
    A539
    Figure US20040054187A1-20040318-C00428
    A540
    Figure US20040054187A1-20040318-C00429
    A541
    Figure US20040054187A1-20040318-C00430
    A542
    Figure US20040054187A1-20040318-C00431
    A543
    Figure US20040054187A1-20040318-C00432
    A544
    Figure US20040054187A1-20040318-C00433
    A545
    Figure US20040054187A1-20040318-C00434
    A546
    Figure US20040054187A1-20040318-C00435
    A547
    Figure US20040054187A1-20040318-C00436
    A548
    Figure US20040054187A1-20040318-C00437
    A549
    Figure US20040054187A1-20040318-C00438
    A550
    Figure US20040054187A1-20040318-C00439
    A551
    Figure US20040054187A1-20040318-C00440
    A552
    Figure US20040054187A1-20040318-C00441
    A553
    Figure US20040054187A1-20040318-C00442
    A554
    Figure US20040054187A1-20040318-C00443
    A555
    Figure US20040054187A1-20040318-C00444
    A556
    Figure US20040054187A1-20040318-C00445
    A557
    Figure US20040054187A1-20040318-C00446
    A558
    Figure US20040054187A1-20040318-C00447
    A559
    Figure US20040054187A1-20040318-C00448
    A560
    Figure US20040054187A1-20040318-C00449
    A561
    Figure US20040054187A1-20040318-C00450
    A562
    Figure US20040054187A1-20040318-C00451
    A563
    Figure US20040054187A1-20040318-C00452
    A564
    Figure US20040054187A1-20040318-C00453
    A565
    Figure US20040054187A1-20040318-C00454
    A566
    Figure US20040054187A1-20040318-C00455
    A567
    Figure US20040054187A1-20040318-C00456
    A568
    Figure US20040054187A1-20040318-C00457
    A569
    Figure US20040054187A1-20040318-C00458
    A570
    Figure US20040054187A1-20040318-C00459
    A571
    Figure US20040054187A1-20040318-C00460
    A572
    Figure US20040054187A1-20040318-C00461
    A573
    Figure US20040054187A1-20040318-C00462
    A574
    Figure US20040054187A1-20040318-C00463
    A575
    Figure US20040054187A1-20040318-C00464
    A576
    Figure US20040054187A1-20040318-C00465
    A577
    Figure US20040054187A1-20040318-C00466
    A578
    Figure US20040054187A1-20040318-C00467
    A579
    Figure US20040054187A1-20040318-C00468
    A580
    Figure US20040054187A1-20040318-C00469
    A581
    Figure US20040054187A1-20040318-C00470
    A582
    Figure US20040054187A1-20040318-C00471
    A583
    Figure US20040054187A1-20040318-C00472
    A584
    Figure US20040054187A1-20040318-C00473
    A585
    Figure US20040054187A1-20040318-C00474
    A586
    Figure US20040054187A1-20040318-C00475
    A587
    Figure US20040054187A1-20040318-C00476
    A588
    Figure US20040054187A1-20040318-C00477
    A589
    Figure US20040054187A1-20040318-C00478
    A590
    Figure US20040054187A1-20040318-C00479
  • A more preferred value for L[0201] 2 is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.
  • A preferred value for X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups. [0202]
  • Another preferred value for X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, or 4) in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4). [0203]
  • Another preferred value for X is an alkylene group having from 6 to 15 carbons atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, 4) in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4). [0204]
  • Another preferred value for X is is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl. [0205]
  • Another preferred value for X is a group of the following formula: [0206]
    Figure US20040054187A1-20040318-C00480
  • wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups. [0207]
  • Another preferred value for X is a group of one of the following formulae: [0208]
    Figure US20040054187A1-20040318-C00481
  • A preferred group of compounds of formula (I) are compounds wherein R[0209] 2 is selected from formula (i) and (iii); and wherein K″ is a bond or methylene.
  • A preferred group of compounds of formula (I) are compounds wherein R[0210] 2 is formula (i); R3 is hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and K″ is a bond or methylene.
  • A preferred group of compounds of formula (I) are compounds wherein R[0211] 2 is formula (iii); R6, R7, and R8 are each hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and K″ is a bond or methylene.
  • A preferred group of compounds are compounds of formula (I) wherein R[0212] 46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR50 where R50 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle.
  • A preferred group of compounds are compounds of formula (I) wherein L[0213] 2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl —SO2-heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • A more preferred group of compounds are compounds of formula (I) wherein L[0214] 2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • A preferred group of compounds are compounds of formula (I) wherein L[0215] 2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • A preferred group of compounds are compounds of formula (I) wherein L is a group of formula (d) wherein at least one of R[0216] 46 and R47 individually, or R46 and R47 taken together, is a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • A preferred group of compounds are compounds of formula (I) wherein L[0217] 2 is a group of formula (d) wherein R46 is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and R47 is alkyl, substituted alkyl, acyl, or —COOR50.
  • A preferred group of compounds are compounds of formula (I) wherein L[0218] 2 is a group of formula (d) wherein R46 is alkyl that is substituted by a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • A preferred group of compounds are compounds of formula (I) wherein L[0219] 2 is a group of formula (d) wherein R46 is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NRaRb, wherein Ra and Rb may be the same or different and and are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclic.
  • A preferred group of compounds are compounds of formula (I) wherein L[0220] 2 is a group of formula (d) wherein R46 is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl —SO2-heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • A preferred group of compounds are compounds of formula (I) wherein L[0221] 2 is a group of formula (d) wherein R46 is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R46 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • A preferred group of compounds are compounds of formula (I) wherein R[0222] 46 and R47 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • A preferred group of compounds are compounds of formula (I) wherein R[0223] 46 and R47 together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).
  • A preferred group of compounds of formula (I) are compounds wherein: A is an aryl or a heteroaryl ring; B″ is —NRa— wherein Ra is hydrogen, alkyl, or substituted alkyl; R[0224] 1 is hydrogen or alkyl; R2 is selected from a group consisting of formula (i), (ii), (iii), or “Het”:
  • wherein: - - - is an optional double bond; n, is an integer of from 1 to 4; n[0225] 2 is an integer of from 1 to 3; V is —CH—, —O—, —S(O)n3— (where n3 is an integer of from 0 to 2), or —NR4— (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); “Het” is a heteroaryl ring which optionally attaches the ligand to a linker; R3 is hydrogen, alkyl, amino, substituted amino, —OR8 (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker; R5 is hydrogen, alkyl, amino, substituted amino, —ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker; R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; K is a bond or an alkylene group; K″ is a bond, —C(O)—, —S(O)n4— (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is a heterocycloamino group which optionally attaches the ligand to a linker; provided that at least one of the R5, R6, R7, R8, “Het”, or the heterocycloamino group attaches the ligand to a linker.
  • A preferred compound of formula (I) is a compound of Formula (Ia): [0226]
    Figure US20040054187A1-20040318-C00482
  • wherein A, R[0227] 1, R2, K, K″, B, X, R46 and R47 are as defined herein.
  • For a compound of Formula (Ia) a preferred group of compounds is that wherein A is phenyl or pyridine; and K and K″ are bond. [0228]
  • For a compound of Formula (Ia) another preferred group of compounds is that wherein A is phenyl or pyridine; R[0229] 2 is phenyl; and K and K″ are bond.
  • For a compound of Formula (Ia) another preferred group of compounds is that wherein B has any of the preferred values identified herein. [0230]
  • The invention also provides a compound of formula (IV): [0231]
    Figure US20040054187A1-20040318-C00483
  • wherein L[0232] 2 is an organic group comprising at least one (e.g. 1, 2, 3, or 4) primary, secondary, or tertiary amines. Typically, the amine of L2 should be basic, having a pH of at least about 5, and preferably at least about 6, more preferably at least about 7. The nature of the group L2 is not critical provided the compound has suitable properties (e.g. solubility, stability, and toxicity) for its intended use (e.g. as a drug or as a pharmacological tool). Typically the group L2 will have a molecular weight below 500 and preferably below about 300. Additionally, the group L2 preferably comprises 5 or fewer hydrogen bond donors (e.g. OH, —NHR—, and —C(═O)NHR—) and ten or fewer hydrogen bond acceptors (e.g. —O—, —NRR—, and —S—). Preferably, the nitrogen of B shown in formula (IV) is separated from an amine of the group L2 by about 15 angstroms to about 75 angstroms (based on conventionally acceptable bond lengths and angles). More preferably, the nitrogen of B is separated from an amine of the group L2 by about 25 angstroms to about 50 angstroms. Preferred compounds of formula (IV) also have a log D between about −3 and about 5. Using the above parameters, one skilled in the art can readily determine compounds of formula (IV) possessing the desired properties for an intended use.
  • General Synthetic Schemes [0233]
  • Compounds of this invention can be made by the methods depicted in the reaction schemes shown below. [0234]
  • The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., U.S.A.), Bachem (Torrance, Calif., U.S.A.), Emka-Chemie, or Sigma (St. Louis, Mo., U.S.A.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [0235]
  • The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. [0236]
  • Furthermore, 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. [0237]
  • Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, [0238] Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. [0239]
  • Preparation of a Compound of Formula (I) [0240]
  • In general, compounds of Formula (I) can be prepared as illustrated and described in Schemes A. [0241]
    Figure US20040054187A1-20040318-C00484
  • A compound of Formula (I) is prepared by covalently attaching one equivalent of a compound of formula 1 with a compound of formula 2 where X is a linker as defined herein, FG[0242] 1 is a functional group, FG2 is a functional group that is complimentary to FG1, PG is a protecting group, and FG2PG is a protected functional group, to give an intermediate of formula (II). Deprotection of the functional group on the linker, followed by reaction of resulting compound 3 with one equivalent of compound 4, then provides a compound of Formula (I). The reaction conditions used to link compounds 1 and 4 to compound 2 and 3 depend on the nature of the functional groups on compounds 1, 2, 3 and 4 which in turn depend on the type of linkage desired. Examples of the functional groups and the reaction conditions that can be used to generate a specific linkage is described below.
    TABLE I
    Representative Complementary Binding Chemistries
    First Reactive Group Second Reactive Group Linkage
    carboxyl amine amide
    sulfonyl halide amine sulfonamide
    hydroxyl alkyl/aryl halide ether
    hydroxyl isocyanate urethane
    amine epoxide β-hydroxyamine
    amine alkyl/aryl halide alkylamine
    hydroxyl carboxyl ester
  • Reaction between a carboxylic acid of either the linker or the ligand and a primary or secondary amine of the ligand or the linker in the presence of suitable, well-known activating agents such as dicyclohexylcarbodiimide, results in formation of an amide bond covalently linking the ligand to the linker; reaction between an amine group of either the linker or the ligand and a sulfonyl halide of the ligand or the linker, in the presence of a base such as triethylarnine, pyridine, and the like, results in formation of a sulfonamide bond covalently linking the ligand to the linker; and reaction between an alcohol or phenol group of either the linker or the ligand and an alkyl or aryl halide of the ligand or the linker in the presence of a base such as triethylamine, pyridine, and the like, results in formation of an ether bond covalently linking the ligand to the linker. [0243]
  • Suitable dihydroxyl and dihalo starting materials useful for incorporating a group X into a compound of the invention are shown in the following table. Preferably, an alcohol is reacted with a ligand bearing a leaving group to provide an ether bond, while a dihalo compound is preferably reacted with an amine of the ligand to form a subatituted amine. [0244]
    No. X
    X1
    Figure US20040054187A1-20040318-C00485
    X2
    Figure US20040054187A1-20040318-C00486
    X3
    Figure US20040054187A1-20040318-C00487
    X4
    Figure US20040054187A1-20040318-C00488
    X5
    Figure US20040054187A1-20040318-C00489
    X6
    Figure US20040054187A1-20040318-C00490
    X7
    Figure US20040054187A1-20040318-C00491
    X8
    Figure US20040054187A1-20040318-C00492
    X9
    Figure US20040054187A1-20040318-C00493
    X10
    Figure US20040054187A1-20040318-C00494
    X11
    Figure US20040054187A1-20040318-C00495
    X12
    Figure US20040054187A1-20040318-C00496
    X13
    Figure US20040054187A1-20040318-C00497
    X14
    Figure US20040054187A1-20040318-C00498
    X15
    Figure US20040054187A1-20040318-C00499
    X16
    Figure US20040054187A1-20040318-C00500
    X17
    Figure US20040054187A1-20040318-C00501
    X18
    Figure US20040054187A1-20040318-C00502
    X19
    Figure US20040054187A1-20040318-C00503
    X20
    Figure US20040054187A1-20040318-C00504
    X21
    Figure US20040054187A1-20040318-C00505
    X22
    Figure US20040054187A1-20040318-C00506
    X23
    Figure US20040054187A1-20040318-C00507
    X24
    Figure US20040054187A1-20040318-C00508
    X25
    Figure US20040054187A1-20040318-C00509
    X26
    Figure US20040054187A1-20040318-C00510
    X27
    Figure US20040054187A1-20040318-C00511
    X28
    Figure US20040054187A1-20040318-C00512
    X29
    Figure US20040054187A1-20040318-C00513
    X30
    Figure US20040054187A1-20040318-C00514
    X31
    Figure US20040054187A1-20040318-C00515
    X32
    Figure US20040054187A1-20040318-C00516
    X33
    Figure US20040054187A1-20040318-C00517
    X34
    Figure US20040054187A1-20040318-C00518
    X35
    Figure US20040054187A1-20040318-C00519
    X36
    Figure US20040054187A1-20040318-C00520
    X37
    Figure US20040054187A1-20040318-C00521
    X38
    Figure US20040054187A1-20040318-C00522
    X39
    Figure US20040054187A1-20040318-C00523
    X40
    Figure US20040054187A1-20040318-C00524
    X41
    Figure US20040054187A1-20040318-C00525
    X42
    Figure US20040054187A1-20040318-C00526
    X43
    Figure US20040054187A1-20040318-C00527
    X44
    Figure US20040054187A1-20040318-C00528
    X45
    Figure US20040054187A1-20040318-C00529
    X46
    Figure US20040054187A1-20040318-C00530
    X47
    Figure US20040054187A1-20040318-C00531
    X48
    Figure US20040054187A1-20040318-C00532
    X49
    Figure US20040054187A1-20040318-C00533
    X50
    Figure US20040054187A1-20040318-C00534
    X51
    Figure US20040054187A1-20040318-C00535
    X52
    Figure US20040054187A1-20040318-C00536
    X53
    Figure US20040054187A1-20040318-C00537
    X54
    Figure US20040054187A1-20040318-C00538
    X55 HOCH2(CF2)8CH2OH
    X56
    Figure US20040054187A1-20040318-C00539
    X57
    Figure US20040054187A1-20040318-C00540
    X58
    Figure US20040054187A1-20040318-C00541
    X59
    Figure US20040054187A1-20040318-C00542
    X60
    Figure US20040054187A1-20040318-C00543
    X61
    Figure US20040054187A1-20040318-C00544
    X62
    Figure US20040054187A1-20040318-C00545
    X63
    Figure US20040054187A1-20040318-C00546
    X64
    Figure US20040054187A1-20040318-C00547
    X65
    Figure US20040054187A1-20040318-C00548
    X66
    Figure US20040054187A1-20040318-C00549
    X67
    Figure US20040054187A1-20040318-C00550
    X68
    Figure US20040054187A1-20040318-C00551
    X69 HOCH2(CH2)4CH2OH
    X70
    Figure US20040054187A1-20040318-C00552
    X71
    Figure US20040054187A1-20040318-C00553
    X72
    Figure US20040054187A1-20040318-C00554
    X73
    Figure US20040054187A1-20040318-C00555
    X74
    Figure US20040054187A1-20040318-C00556
    X75
    Figure US20040054187A1-20040318-C00557
    X76
    Figure US20040054187A1-20040318-C00558
    X77
    Figure US20040054187A1-20040318-C00559
    X78
    Figure US20040054187A1-20040318-C00560
    X79
    Figure US20040054187A1-20040318-C00561
    X80
    Figure US20040054187A1-20040318-C00562
    X81
    Figure US20040054187A1-20040318-C00563
    X82
    Figure US20040054187A1-20040318-C00564
    X83
    Figure US20040054187A1-20040318-C00565
    X84
    Figure US20040054187A1-20040318-C00566
    X85
    Figure US20040054187A1-20040318-C00567
    X86
    Figure US20040054187A1-20040318-C00568
    X87
    Figure US20040054187A1-20040318-C00569
    X88
    Figure US20040054187A1-20040318-C00570
    X89
    Figure US20040054187A1-20040318-C00571
    X90
    Figure US20040054187A1-20040318-C00572
    X91
    Figure US20040054187A1-20040318-C00573
    X92
    Figure US20040054187A1-20040318-C00574
    X93
    Figure US20040054187A1-20040318-C00575
    X94
    Figure US20040054187A1-20040318-C00576
    X95
    Figure US20040054187A1-20040318-C00577
    X96
    Figure US20040054187A1-20040318-C00578
    X97
    Figure US20040054187A1-20040318-C00579
    X98
    Figure US20040054187A1-20040318-C00580
    X99
    Figure US20040054187A1-20040318-C00581
    X100 HOCH2(CF2)3CH2OH
  • Typically, a compound selected for use as a ligand will have at least one functional group, such as an amino, hydroxyl, thiol or carboxyl group and the like, which allows the compound to be readily coupled to the linker. Compounds having such functionality are either known in the art or can be prepared by routine modification of known compounds using conventional reagents and procedures. [0245]
  • A compound of formula (a) wherein A is phenyl, pyridyl, and the like can be prepared as described in EP 747 355 and as described by Naito, R. et al., [0246] Chem. Pharm. Bull., 1998, 46(8), 1286.
  • Scheme B [0247]
  • L1—H+ Ra—X—L2 →  (I)
  • A compound of formula (I) wherein L[0248] 1 comprises a nitrogen that is bonded to X, can be prepared by alkylating a corresponding compound of formula L1—H wherein —H is bound to the nitrogen, with a corresponding compound of Ra—X—L2 wherein X and L2 have any of the values defined herein and Ra is a suitable leaving group. Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York. For example, Ra can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
  • Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L[0249] 1 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L1—H with a compound of Ra—X—L2 wherein X and L2 have any of the values defined herein and Ra is a suitable leaving group.
  • The invention also provides a compound of formula L[0250] 1—H wherein L1 has any of the values defined herein. The following compounds are preferred compounds of formula L1—H:
    Figure US20040054187A1-20040318-C00582
  • The invention also provides a compound of formula R[0251] a—X—L2 wherein X, and L2 have any of the values defined herein and Ra is a suitable leaving group. The compound of formula L1—H can also be alkylated by treatment with an aldehyde of formula L2—V—CHO (wherein —V—CH2— is equivalent to —X—), under reductive alkylation conditions. Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).
  • Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L[0252] 1 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L1—H with a compound of formula L2—V—CHO (wherein —V—CH2— has any of the values for —X— described herein).
  • Scheme C [0253]
  • L1—X—Ra+H—L2 →  (I)
  • A compound of formula (I) wherein L[0254] 2 comprises a nitrogen that is bonded to X, can be prepared by alkylating a corresponding compound of formula L2—H wherein —H is bound to the nitrogen, with a corresponding compound of L1—X—Ra wherein X and L1 have any of the values defined herein and Ra is a suitable leaving group. Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York. For example, Ra can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
  • Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L[0255] 2 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L2—H with a compound of L1—X—Ra wherein X and L1 have any of the values defined herein and Ra is a suitable leaving group.
  • The compound of formula L[0256] 2—H can also be alkylated by treatment with an aldehyde of formula L1—V—CHO (wherein —V—CH2— is equivalent to —X—), under reductive alkylation conditions. Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).
  • Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L[0257] 2 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L2—H with a compound of formula L1—V—CHO (wherein —V—CH2— has any of the values for —X— described herein).
  • It will be understood that the alkylation reactions in Schemes B and C can optionally be carried out using suitably protected derivatives of L[0258] 1—H, L2—H, L1—X—Ra, Ra—X—L2, L1V—CHO, and L2—V—CHO. Suitable protecting groups as well as conditions for their incorporation and removal are known in the art (for example, see Greene, T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis” second edition, 1991, New York, John Wiley & sons, Inc.). Thus, a compound of formula (I) can also be prepared by deprotecting a corresponding compound of formula (I) bearing one or more protecting groups.
  • Accordingly, the invention provides a method for preparing a compound of formula (I) comprising deprotecting a corresponding compound of formula (I) that bears one or more protecting groups. The invention also provides an intermediate compound of formula (I) that bears one or more protecting groups. [0259]
  • Combinatorial Synthesis [0260]
  • Compounds of formula (I) can conveniently be prepared using combinatorial synthesis methods (e.g. solid phase and solution phase combinatorial synthesis methods) that are known in the art. For example, compounds of formula (I) can be prepared using combinatorial methods like those escribed in International Patent Application Publication Number WO 99/64043. [0261]
  • Utility, Testing, and Administration [0262]
  • Utility [0263]
  • The compounds of this invention are muscarinic receptor antagonists or agonists. A preferred sub-groug of compounds of the invention are M[0264] 2 muscarinic receptor antagonists. Accordingly, the compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by these receptors such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, hyper salvation syndromes, and the like.
  • Testing [0265]
  • The ability of the compounds of formula (I) to inhibit a muscarinic receptor (e.g. the M[0266] 2 or M3 subtype) may be demonstrated using a variety of in vitro assays and in vivo assays known in the field, or may be demonstrated using an assay described in biological examples 1-6 below.
  • Pharmaceutical Formulations [0267]
  • When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intravesicular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. [0268]
  • This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. [0269]
  • In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. [0270]
  • Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. [0271]
  • The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, usually about 0.1 to about 500 mg, more usually about 1 to about 50 mg, of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of Formula (I) above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s). [0272]
  • The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically 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. [0273]
  • For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention. [0274]
  • The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [0275]
  • The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. [0276]
  • Compositions for inhalation or insulation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.[0277]
    • EXAMPLES
  • The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. [0278]
  • In the examples below, the following abbreviations have the following meanings. Unless otherwise stated, all temperatures are in degrees Celsius. If an abbreviation is not defined, it has its generally accepted meaning. [0279]
  • g=gram [0280]
  • mg=milligram [0281]
  • min=minute [0282]
  • ml=milliliter [0283]
  • mmol=millimol [0284]
    • Synthetic Examples Example 1
  • The intermediate compound of formula 1B was prepared as follows. [0285]
    Figure US20040054187A1-20040318-C00583
  • Biphenyl-2-isocynate (50 g, 256 mmol) was dissolved in 400 mL anhydrous acetonitrile in a 2L rbf at room temperature. After cooling to 0 C. using an ice bath, a solution of 4-amino-N-benzylpiperidine (48.8 g, 256 mmol) dissolved in 400 mL anhydrous acetonitrile was added over 5 minutes. Precipitate was observed immediately. After 15 minutes, an additional 600 mL anhydrous acetonitrile was added to permit stirring of the viscous solution for 12 h at 35 C. The solids were filtered, and washed with cold acetonitrile then dried under vacuum, yielding a colorless solid (100 g, 98%). This material was characterized by [0286] 1H-NMR, 13C-NMR and MS.
  • Compound 1A (20 g, 52 mmol) was dissolved in 800 mL of a 3:1 mixture of anhydrous methanol to anhydrous DMF. Aqueous HCl was added (0.75 mL of 37% conc solution, 7.6 mmol) and nitrogen gas bubbled through the solution vigorously for 20 min. Pd(OH)2 (Pearlman's catalyst, 5 g) was added under a stream of nitrogen. A large balloon containing H2 gas was placed and the solution allowed to stir for 4 d. The solution was passed twice through pads of celite to remove the catalyst, and the solution evaporated to dryness under vacuum to yield a colorless solid (13 g, 85%). This material was characterized by [0287] 1H-NMR, 13C-NMR and MS.
  • Following the procedures described above but substituting the appropriate starting materials, the compounds of the invention (formula (VI)) listed in Table A below were prepared. Unless otherwise noted, for the compounds in Tables A-F, L[0288] 2 is attached to X through the secondary non-aromatic amine of L2.
    TABLE A
    (VI)
    Figure US20040054187A1-20040318-C00584
    Compound L2 Mass Spec Found
    1 A224 411.6
    2 A87 488.6
    3 A172 517.7
    4 A90 514.7
    5 A141 607.8
    6 A169 517.7
    7 A164 517.78
    8 A208 451.6
    9 A199 467.6
    10 A23 534.6
    11 A70 542.7
    12 A73 542.7
    13 A156 605.8
    14 A95 511.7
    15 A115 467.6
    16 A156 605.8
    17 A516 487.7
    18 A364 511.7
    19 A96 485.6
    20 A508 537.7
    21 A509 537.7
    22 A190 505.7
    23 (135) 616.8
    24 A51 532.7
    25 A524 496.7
    26 A410 542.7
    27 A368 516.7
    28 A84 515.7
    29 A65 516.7
    30 A193 548.8
    31 A142 604.8
    32 A177 556.8
    33 A68 515.7
    34 A501 529.7
    35 A525 574.7
    36 A168 554.7
    37 A437 604.8
    38 A61 536.7
    39 A117 480.6
    40 A166 542.7
    41 78 520.7
    42 A49 583.7
    43 A367 514.7
    44 A526 572.7
    45 A229 547.7
    46 A239 427.6
    47 A179 483.7
    48 A182 437.6
    49 A55 467.6
    50 A510 514.7
    51 A502 502.7
    52 A43 551.7
    53 A218 518.7
    54 A123 494.6
    55 A126 538.7
    56 A134 534.6
    57 A120 480.6
    58 A157 517.7
    59 A396 533.7
    60 A25 569.7
    61 A83 559.7
    62 A161 469.6
    63 A11* 571.1
    64 A420 554.7
    65 A135 541.7
    66 A411 543.7
    67 A88 531.7
    68 A386 527.7
    69 A404 538.7
    70 A72 529.7
    71 A26 569.8
    72 A75 513.7
    73 A419 553.7
    74 A375 517.7
    75 A20 527.7
    76 A427 571.7
    77 A527 619.8
    78 A9 485.6
    79 A520 467.6
    80 A19 453.6
    81 A513 551.7
    82 A10 517.7
    83 A110 466.6
    84 A4 494.6
    85 A19 453.6
    86 A103 530.7
    87 A60 536.7
    88 A131 600.7
    89 A114 440.6
    90 A197 468.6
    91 A151 451.6
    92 A195 463.6
    93 A528 495.7
    94 A347 487.7
    95 A328 467.6
    96 A22 526.7
    97 A336 480.6
    98 A77 585.8
    99 A145 452.6
    100 A211 550.7
  • Following the procedures described above but substituting appropriate starting materials, the compounds of the invention (formula (VII)) listed in Table B below were prepared. [0289]
    TABLE B
    (VII)
    Figure US20040054187A1-20040318-C00585
    Compound L2 Mass Spec Found
    101 A224 395.6
    102 A87 472.6
    103 A529 381.5
    104 A530 533.1
    105 A172 501.7
    106 A141 591.8
    107 A164 501.7
    108 A199 451.6
    109 A70 526.7
    110 A73 526.7
    111 A156 589.8
    112 A230 521.7
    113 A391 515.7
    114 A95 495.7
    115 A156 589.8
    116 A516 471.7
    117 A97 495.7
    118 A96 469.6
    119 A508 521.7
    120 A509 521.7
    121 A190 489.7
    122 A435 600.8
    123 A410 526.7
    124 A84 499.7
    125 A193 532.8
    126 A142 588.8
    127 A177 540.8
    128 A68 499.7
    129 A433 588.8
    130 A166 526.7
    131 A31 498.7
    132 A526 556.7
    133 A436 616.1
    134 A50 602.1
    135 A132 505.7
    136 A231 526.5
    137 A229 531.7
    138 A401 522.1
    139 A373 501.7
    140 A90 498.7
    141 A502 486.7
    142 A43 535.7
    143 A43@ 536.7
    144 A576 522.7
    145 A374 501.7
    146 A17 511.7
    147 A21 517.7
    148 A83 543.7
    149 A531 538.7
    150 A125 525.7
    151 A210 527.7
    152 A88 515.7
    153 A78 511.7
    154 A404 522.7
    155 A72 513.7
    156 A26 553.8
    157 A75 497.7
    158 A419 537.7
    159 A527 603.8
    160 A520 451.6
    161 A513 535.7
    162 A164 501.7
    163 A4 478.7
    164 A521 515.7
    165 A60 520.7
    166 A522 584.7
    167 A192 551.7
    168 A122 533.7
    169 A109 499.7
    170 A383 507.7
    171 A395 516.7
    172 A503 594.8
    173 A528 479.7
    174 A99 471.7
    175 A22 510.7
    176 A532 569.8
  • Following the procedures described above but substituting appropriate starting materials, the compounds of the invention (formula (VIII)) listed in Table C below were prepared. [0290]
    TABLE C
    (VIII)
    Figure US20040054187A1-20040318-C00586
    Compound L2 Mass Spec Found
    177 A508 607.8
    178 A509 607.8
    179 A501 599.8
    180 A90 584.8
    181 A502 572.8
    182 A43 621.8
    183 A513 621.8
    184 A503 681.0
    185 A87 558.8
    186 A164 587.8
    187 A90 584.8
    188 A90@ 585.8
    189 A10 587.8
    190 A172 587.8
    191 A208 521.7
    192 A330 537.8
    193 A70 612.9
    194 A73 612.9
    195 A8 601.8
    196 A95 581.8
    197 A115 537.8
    198 A516 557.8
    199 A97 581.8
    200 A96 555.8
    201 A358 575.9
    202 A517 687.0
    203 A62 612.9
    204 A74 586.8
    205 A84 585.8
    206 A65 586.8
    207 A193 618.9
    208 A142 674.9
    209 A177 626.9
    210 A501 585.8
    211 A217 644.8
    212 A168 624.9
    213 A166 612.9
    214 A31 584.8
    215 A28 642.9
    216 A104 702.3
    217 A144 608.2
    218 A373 587.8
    219 A90@ 585.8
    220 A43@ 622.8
    221 A576 608.8
    222 A374 587.8
    223 A17 597.9
    224 A396 603.8
    225 A214 625.9
    226 A83 629.8
    227 A418 622.9
    228 A135 611.6
    229 A210 613.9
    230 A88 601.8
    231 A404 608.8
    232 A121 624.8
    233 A520 537.8
    234 A164 587.8
    235 A4 564.8
    236 A521 601.8
    237 A60 606.9
    238 A522 670.9
    239 A109 585.8
    240 A22 596.8
    241 A532 655.9
    242 A397 604.7
    243 A120 550.8
    244 A533 509.7
    245 A505* 626.9
    246 A506 598.8
    247 A431 659.9
    248 A388 597.9
    249 A366 583.8
    250 A534 578.8
    251 A417 622.9
    252 A577 575.8
    253 A319 536.7
    254 A381 593.8
    255 A338 550.8
    256 A329 537.8
    257 A403 608.8
    258 A333 549.8
  • Following the procedures described above but substituting appropriate starting materials, the compounds of the invention (formula (IX)) listed in Table D below were prepared. [0291]
    TABLE D
    (IX)
    Figure US20040054187A1-20040318-C00587
    Compound L2 Mass Spec Found
    259 A508 591.8
    260 A509 591.8
    261 A501 583.8
    262 A510 568.8
    263 A502 556.8
    264 A43 605.8
    265 A512 581.8
    266 A513 605.8
    267 A503 665.0
    268 A223 542.8
    269 A224 465.7
    272 A535 661.9
    273 A536 571.8
    274 A537 571.8
    275 A306 505.7
    276 A580 521.8
    277 A578 588.7
    278 A538 596.9
    279 A539 596.9
    280 A321 520.8
    281 A156 659.9
    282 A400 591.9
    283 A8 585.8
    284 A363 565.8
    285 A359 560.8
    286 A324 521.8
    287 A156 659.9
    288 A516 541.8
    289 A364 565.8
    290 A346 539.8
    291 A581 559.9
    292 A517 671.0
    293 A394 586.8
    294 A410 596.9
    295 A368 570.8
    296 A84 569.8
    297 A369 570.8
    298 A193 602.9
    299 A432 658.9
    300 A423 610.9
    301 A68 569.8
    302 A525 628.8
    303 A168 608.9
    304 A45 658.9
    305 A398 590.8
    306 A117 534.8
    307 A166 596.9
    308 A378 574.9
    309 A198 523.8
    310 A137 534.8
    311 A316 520.7
    312 A339 534.8
    313 A322 520.8
    314 A352 548.8
    315 A430 637.9
    316 A384 568.8
    317 A28 626.9
    318 A436 686.3
    319 A50 672.2
    320 A132 575.8
    321 A205 550.8
    322 A154 566.8
    323 A413 601.8
    324 A144 592.2
    325 A301 481.7
    326 A344 537.8
    327 A182 491.7
    328 A373 571.18
    329 A340 535.8
    330 A325 521.8
    331 A94 567.8
    332 A218 572.8
    333 A348 548.8
    334 A519 588.9
    335 A126 592.8
    336 A397 588.7
    337 A155 571.18
    338 A308 507.7
    339 A387 581.9
    340 A311 521.8
    341 A21 587.8
    342 A426 623.9
    343 A422 609.9
    344 A424 613.8
    345 A418 606.9
    346 A161 523.7
    347 A11 625.9
    348 A420 608.8
    349 A406 595.8
    350 A210 597.9
    351 A374 585.8
    352 A386 581.9
    353 A540 592.8
    354 A72 583.8
    355 A26 623.9
    356 A365 567.8
    357 A419 607.9
    358 A341 535.8
    359 A412 599.8
    360 A121 608.8
    361 A375 571.8
    362 A385 581.8
    363 A427 625.9
    364 A527 674.0
    365 A345 539.8
    366 A327 521.8
    367 A583 507.7
    368 A227 673.0
    369 A312 511.7
    370 A4115 603.8
    371 A376 571.8
    372 A98 592.8
    373 A317 520.7
    374 A4 548.8
    375 A165 535.7
    376 A380 577.8
    377 A541 585.8
    378 A584 589.8
    379 A311 507.7
    380 A521 585.8
    381 A390 584.9
    382 A399 590.9
    383 A131 654.9
    384 A27 495.7
    385 A204 548.8
    386 A122 603.9
    387 A350 548.8
    388 A425 617.9
    389 A109 569.8
    390 A542 664.0
    391 A114 494.7
    392 A331 522.7
    393 A235 577.8
    394 A543 586.8
    395 A151 505.8
    396 A313 517.7
    397 A528 549.9
    398 A99 541.8
    399 A328 521.8
    400 A384 580.8
    401 A314 519.8
    402 A335 534.8
    403 A360 562.2
    404 A77 639.9
    405 A145 506.7
    406 A71 563.8
    407 A124 523.7
    408 A377 573.8
    409 A416 604.8
    410 A329 521.8
    411 A43 606.8
    412 A307 505.8
    413 A397 588.7
    414 A337# 534.8
    415 A303 493.7
    416 A544 610.9
    417 A506 582.8
    418 A431 643.9
    419 A388 581.9
    420 A366 567.8
    421 A523 562.8
    422 A545 606.9
    423 A577 559.8
    424 A319 520.7
    425 A381 577.8
    426 A351 548.8
    427 A338 534.8
    428 A362 563.8
    429 A507 477.7
    430 A402 592.8
    431 A403 592.8
    432 A315 519.8
    433 A333 533.8
  • Following the procedures described above but substituting appropriate starting materials, the compounds of the invention (formula (X)) listed in Table E below were prepared. [0292]
    TABLE E
    (X)
    Figure US20040054187A1-20040318-C00588
    Compound L2 Mass Spec Found
    434 A130 525.7
    435 A105 521.8
    436 A356 571.8
    437 A415 617.8
    438 A579 585.8
    439 A98 606.8
    440 A317 534.8
    441 A349 562.8
    442 A465 549.8
    443 A380 591.8
    444 A546 599.8
    445 A547 548.8
    446 A548 587.8
    447 A386 676.9
    448 A311 521.8
    449 A521 599.9
    450 A127 490.7
    451 A390 598.9
    452 A399 604.9
    453 A342 550.8
    454 A27 509.7
    455 A549 562.9
    456 A550 635.9
    457 A238 617.9
    458 A350 562.8
    459 A425 631.9
    460 A109 583.9
    461 A114 508.7
    462 A331 536.8
    463 A551 585.8
    464 A235 591.9
    465 A395 600.8
    466 A13 615.8
    467 A552 507.8
    468 A151 519.8
    469 A313 531.8
    470 A35 507.8
    471 A99 555.8
    472 A328 535.8
    473 A22 594.9
    474 A314 533.8
    475 A336 548.8
    476 A228 684.0
    477 A360 576.2
    478 A145 520.7
    479 A302 505.8
    480 A71 577.8
    481 A553 656.9
    482 A124 537.8
    483 A554 587.8
    484 A416 618.9
    485 A555 625.9
    486 A556 701.0
    487 A557 716.0
    488 A558 638.9
    489 A559 624.8
    490 A560 654.0
    491 A561 654.0
    492 A508 605.8
    493 A509 605.8
    494 A501 597.9
    495 A510 582.8
    496 A502 570.8
    497 A43 619.9
    498 A512 595.8
    499 A513 619.9
    500 A503 679.0
    501 A504 556.8
    502 A514 613.9
    503 A402 606.9
    504 A403 606.9
    505 A397 602.8
    506 A337 548.8
    507 A303 507.7
    508 A505 624.9
    509 A506 596.9
    510 A431 658.0
    511 A388 595.9
    512 A366 581.9
    513 A523 576.8
    514 A417 620.9
    515 A577 573.8
    516 A319 534.8
    517 A381 591.8
    518 A351 562.8
    519 A338 548.8
    520 A362 577.8
    521 A507 491.7
    522 A324 535.8
    523 A315 533.8
    524 A333 547.8
    525 A427 718.8
    526 A402 685.8
    527 A562 506.7
    528 A563 506.7
    529 A564 520.8
    530 A565 731.0
    531 A370 585.8
    532 A371 585.8
    533 A372 585.8
    534 A587 519.7
    535 A330 535.8
    536 A320 534.8
    537 A578 602.8
    538 A588 548.8
    539 A538 610.9
    540 A539 610.9
    541 A321 534.8
    542 A156 674.0
    543 A141 675.9
    544 A569 687.0
    545 A400 605.9
    546 A391 599.9
    547 A363 579.8
    548 A359 574.9
    549 A311 535.8
    550 A570 602.9
    551 A515 674.0
    552 A178 680.0
    553 A364 579.8
    554 A346 553.8
    555 A358 573.9
    556 A517 685.0
    557 A571 634.0
    558 A51 600.8
    559 A64 564.8
    560 A67 619.9
    561 A62 610.9
    562 A180 617.9
    563 A74 584.8
    564 A84 583.8
    565 A65 584.8
    566 A193 616.9
    567 A432 672.9
    568 A200 591.9
    569 A177 624.9
    570 A572 632.0
    571 A174 603.9
    572 A68 583.8
    573 A525 642.9
    574 A168 622.9
    575 A45 673.0
    576 A61 604.8
    577 A117 548.8
    578 A166 610.9
    579 A378 588.9
    580 A137 548.8
    581 A34 534.8
    582 A93 548.8
    583 A59 562.9
    584 A585 651.9
    585 A31 582.8
    586 A28 640.9
    587 A436 700.3
    588 A50 686.3
    589 A3 675.0
    590 A379 589.8
    591 A573 610.7
    592 A355 564.8
    593 A413 615.9
    594 A401 606.3
    595 A301 495.7
    596 A179 551.8
    597 A82 551.8
    598 A12 585.8
    599 A55 535.8
    600 A133 607.9
    601 A94 581.8
    602 A100 570.8
    603 A123 562.8
    604 A589 606.9
    605 A134 602.8
    606 A203 548.8
    607 A17 595.9
    608 A66 535.8
    609 A214 623.9
    610 A574 627.9
    611 A154 585.8
    612 A6 636.9
    613 A185 521.8
    614 A2 525.7
    615 A119 569.8
    616 A21 601.8
    617 A25 637.9
    618 A33 620.9
    619 A161 537.8
    620 A11* 639.9
    621 A420 622.9
    622 A135 609.9
    623 A210 611.9
    624 A88 599.9
    625 A72 597.9
    626 A69 521.8
    627 A26 637.9
    628 A365 581.9
    629 A171 621.9
    630 A81 549.8
    631 A412 613.9
    632 A121 622.9
    633 A18 663.9
    634 A232 585.8
    635 A575 670.0
    636 A20 595.8
    637 A153 639.9
    638 A590 688.0
    639 A91 477.7
    640 A9 553.8
    641 A194 535.8
    642 A310 521.8
    643 A227 687.0
  • Following the procedures described above but substituting appropriate starting materials, the compounds of the invention (formula (XI)) listed in Table F below were prepared. [0293]
    TABLE F
    (XI)
    Figure US20040054187A1-20040318-C00589
    Compound L2 Mass Spec Found
    270 A224 609.6
    271 A87 686.7
  • In the above tables *signifies that L[0294] 2 is attached to X through the piperidine nitrogen of L2; @ signifies that L2 is attached to X through the pyridine nitrogen of L2; and #signifies that L2 is attached to X through the pyrrolidine nitrogen of L2.
    • Formulation Examples Example 1
  • Hard gelatin capsules containing the following ingredients are prepared: [0295]
    Quantity
    Ingredient (mg/capsule)
    Active Ingredient 30.0
    Starch 305.0
    Magnesium stearate 5.0
  • The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. [0296]
    • Example 2
  • A tablet Formula is prepared using the ingredients below: [0297]
    Quantity
    Ingredient (mg/tablet)
    Active Ingredient 25.0
    Cellulose, microcrystalline 200.0
    Colloidal silicon dioxide 10.0
    Stearic acid 5.0
  • The components are blended and compressed to form tablets, each weighing 240 mg. [0298]
    • Example 3
  • A dry powder inhaler formulation is prepared containing the following components: [0299]
    Ingredient Weight %
    Active Ingredient 5
    Lactose 95
  • The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. [0300]
    • Example 4
  • Tablets, each containing 30 mg of active ingredient, are prepared as follows: [0301]
    Quantity
    Ingredient (mg/tablet)
    Active Ingredient 30.0 mg
    Starch 45.0 mg
    Microcrystalline cellulose 35.0 mg
    Polyvinylpyrrolidone 4.0 mg
    (as 10% solution in sterile water)
    Sodium carboxymethyl starch 4.5 mg
    Magnesium stearate 0.5 mg
    Talc 1.0 mg
    Total 120 mg
  • The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50° to 60° C. and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. [0302]
    • Example 5
  • Capsules, each containing 40 mg of medicament are made as follows: [0303]
    Quantity
    Ingredient (mg/capsule)
    Active Ingredient 40.0 mg
    Starch 109.0 mg
    Magnesium stearate 1.0 mg
    Total 150.0 mg
  • The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. [0304]
    • Example 6
  • Suppositories, each containing 25 mg of active ingredient are made as follows: [0305]
    Ingredient Amount
    Active Ingredient 25 mg
    Saturated fatty acid glycerides to 2,000 mg
  • The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. [0306]
    • Example 7
  • Suspensions, each containing 50 mg of medicament per 5.0 mL dose are made as follows: [0307]
    Ingredient Amount
    Active Ingredient 50.0 mg
    Xanthan gum 4.0 mg
    Sodium carboxymethyl cellulose (11%)
    Microcrystalline cellulose (89%) 50.0 mg
    Sucrose 1.75 g
    Sodium benzoate 10.0 mg
    Flavor and Color q.v.
    Purified water to 5.0 mL
  • The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. [0308]
    • Example 8
  • A formulation may be prepared as follows: [0309]
    Quantity
    Ingredient (mg/capsule)
    Active Ingredient 15.0 mg
    Starch 407.0 mg
    Magnesium stearate 3.0 mg
    Total 425.0 mg
  • The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities. [0310]
    • Example 9
  • A formulation may be prepared as follows: [0311]
    Ingredient Quantity
    Active Ingredient 5.0 mg
    Corn Oil 1.0 mL
  • Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices (“patches”). Such 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, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated by reference in its entirety. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0312]
  • Other suitable formulations for use in the present invention can be found in [0313] Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
    • Biological Examples Example 1 M2 Muscarinic Receptor In Vitro Binding Assay
  • The M[0314] 2 muscarininc receptor binding activity of compounds of the invention was tested as follows.
  • SF9 cell membranes containing human M[0315] 2 muscarinic receptor was obtained from NEN (Boston, Mass.). In 96-well microtiter plates, eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 μM (4× the final concentration). To 100 μl of compound dilution was added 150 μL M3 receptor membrane preparation in PBS/1.0 mM MgCl2/pH 7.4. 50 μl of 3.2 nM 3H-N-methylscopolamine radioligand was added. The total volume in each well was then 300 μl. The filter plate was pre-blocked using 0.3% PEI for at least 15 minutes, and then washed twice with 200 μl PBS. The assay plate was incubated for 1 hour at room temperature with gentle shaking. The contents of the assay plate were then transferred to the filter plate, and washed three times using 200 μl PBS. About 40 μl of scint was added to each well and then the plate was allowed to sit at room temperature for 2 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 minute per well using a standard protocol on a Packard top counter. The raw data was fit to a standard 4-parameter equation given below and a value of IC50 obtained.
  • Y=(a−d)/(1+(x/c)b)+d where
  • Y=cpm [0316]
  • a=total binding [0317]
  • b=slope [0318]
  • c=IC[0319] 50
  • x=[compound][0320]
  • d=nonspecific binding [0321]
  • Representative compounds of the invention were found to have pK[0322] b values of greater than 6, and to have IC50 values of less than about 50 μm.
  • A similar protocol was used to measure M1, M3, M4 and M5 human muscarinic receptor activity. [0323]
    • Example 2 Rat Heart Muscarinic Receptor In Vitro Binding Assay
  • Tissue (rat heart) muscarininc receptor binding activity of compounds of the invention was tested as follows. [0324]
  • Muscarinic receptor enriched membranes were isolated from whole hearts (Pelfreeze Laboratories). Rat heart tissue was typically prepared as follows. 25 μl of ice cold buffer (20 mM HEPES, 100 mM NaCl/10 mM MgCl[0325] 2 at pH 7.5 with “Complete” protease inhibitor cocktail purchased from Boehringer Mannheim was added into an oakridge tube. To the tube was then added 2 g of rat heart (purchased from Harlan). The contents of the tube were then transferred to a wheaton glass cylinder and homogenized using a Polytron homogenizer (setting 22, 15 seconds ×2), and then transferred back to the oakridge tube, and centrifuged for 10 minutes at 1500 g. The supernatant was removed and then centrifuged for 20 minutes at 45000 g. The supernatant was removed and the pellet resuspended in 5 mL buffer and transferred to a wheaton glass cylinder. This material was then homogenized using a Potter type glass teflon homogenizer with 7-8 passes. The material was then transferred to an oakridge tube and the total volume was brought up to 25 mL. This material was then centrifuged for 20 minutes at 45000 g, and the pellet re-suspended in 2 mL buffer using 2 passes of a teflon homogenizer, and stored at −80° C. until used.
  • A protocol similar to that used for cloned receptor binding was used: Eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 μM (4× the final concentration). To 50 μl of compound dilution in a 96-well assay plate was added an appropriate amount of rat heart membrane (usually 12.5 μl of membrane prep in 87.5 μl of 20 mM HEPES, 100 mM NaCl/10 mM MgCl[0326] 2 at pH 7.5). The amount of membrane added depends in general on the results of signal optimization, and ranges from 6.25-12.5 μl. Last, 50 μl of 2.12 nM 3H-N-methylscopolamine radioligand was added. The total volume in each well was 200 μl. The filter plate was pre-blocked using 0.3% PEI for at least 15 min., and then washed twice with 200 μl PBS. The assay plate was incubated for 1 h at room temperature with gentle shaking. The contents of the assay plate were then transferred to the filter plate, and washed three times using 200 μl PBS. About 40 μl of scint was added to each well and then the plate was allowed to sit at room temperature for 18 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 min., per well using a standard protocol on the Packard counter. The data was fit to normal isotherms and values for inhibition constants were extracted. Representative compounds of the invention were found to have pKb values of greater than 6, and to have IC50 values of less than about 50 μm.
  • A similar procedure was used to measure muscarinic receptor binding at rat submaxillary gland, rat bladder, rat submandibular gland, guinea pig heart, guinea pig submaxillary gland, guinea pig bladder, and guinea pig submandibular gland, as well as in similar human tissues.. [0327]
    • Example 3 Rat Bladder M3 In Vitro Binding Assay
  • Bladder was comprised of both M[0328] 2 and M3 muscarinic receptors. The ratio was typically 4:1 M2:M3. In order to measure binding of test compounds to one of M2 or M3, the other was blocked with a reversible ligand that binds selectively to that receptor. The following example illustrates the procedure for M3 bladder binding.
  • Membranes from rat bladder were prepared in a similar fashion to that used to isolate heart membrane above. Eight serial five-fold dilutions were prepared with the compound to be assayed in compound dilution buffer (20 mM HEPES/100 mM NaCl/10 mM MgCl[0329] 2/4 μM Methoctramine); the highest concentration was typically 4 μM (4× the final concentration). The concentration of methoctramine was sufficient to block >99% of the M2 receptor in bladder, but less than 40% of the M3 receptor in bladder. To 50 μl of compound dilution in a 96-well assay plate was added an appropriate amount of rat heart membrane (usually 25 μl of membrane prep in 75 μl of 20 mM HEPES, 100 mM NaCl/10 mM MgCl2 at pH 7.5). The amount of membrane added depended in general on the results of signal optimization, and ranged from 12.5-25. Last, 50 μl of 2.12 nM 3H-N-methylscopolamine radioligand in compound dilution buffer was added. The total volume in each well was 200 μl. The final concentration of methoctramine was 2 μM. The filter plate was pre-blocked using 0.3% PEI for at least 15 mins., and then washed twice with 200 μl PBS. The assay plate was incubated for 1 hour at room temperature with gentle shaking. The contents of the assay plate was then transferred to the filter plate, and washed three times using 200 μl PBS. About 40 μl of scint was added to each well, the plate was allowed to sit at room temperature for 18 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 minute per well using a standard protocol on the Packard counter. The data was fit to normal isotherms and values for inhibition constants were extracted. Representative compounds of the invention were found to have IC50 values of less than about 500 μm.
  • A similar procedure was used to measure binding at bladder M[0330] 2, but in this case, 2 μM Darifenacin was used to block >99% of the M2 receptor, but minimal M3 receptor.
    • Example 4 Ex Vivo Rat Bladder Contraction Assay
  • The ability of the test compound to inhibit cholinergically stimulated bladder contraction was tested as follows. [0331]
  • Male Sprague-Dawley rats weighing 250-300 g are killed by CO[0332] 2 overdose. The bladder was removed and placed in a petri dish containing Krebs-Henseleit solution at room temperature. The apex and dome areas of the bladder were discarded and the remaining tissue cut into longitudinal strips (4 from each rat). The strips were mounted in an organ bath containing Krebs-Henseleit solution at 37° C., under a resting tension of 0.5 g. The tissues were allowed to equilibrate for 60 min., (washes at 0, 30 and 60 min.). Tension was readjusted to 1 g as necessary. A cumulative concentration response curve to carbachol (10−8 M to 10−5 M (e.g.) in 3-fold increments) was constructed in each tissue. Tissues were then washed every 5 min., for 30 min., and tension readjusted to 1 g. After additional 30 min., muscarinic antagonist (typically 1×10−7 M) or vehicle was added. Thirty minutes after antagonist or vehicle addition, a cumulative concentration response curve to carbachol (10−8M to 10−3M (e.g.)) was constructed. Data from each concentration response curve was expressed as a percentage of the maximum contraction to carbachol. The EC50 values were calculated. The concentration-ratios were calculated taking into account any spontaneous shift in the control tissue. For competitive antagonists, the pKb value was calculated using the following equation: pKb = - log   [ antagonist   concentration ] CR - 1
    Figure US20040054187A1-20040318-M00001
  • Representative compounds of the invention were found to have pK[0333] b values of greater than 5.
    • Example 5 In Vivo Rat Salivation Assay
  • Male Sprague-Dawley rats weighing 250-300 g were anesthetized with pentobarbital (60 mg/kg i.p.). Rats were placed on a heated blanket under a 20 degree incline. A swab was placed in the rat's mouth. Muscarinic antagonist or vehicle was administered i.v. via the tail vein. After 5 min., oxotremorine (0.3 mg/kg) was administered s.c. The swab was discarded and replaced by a pre-weighed swab. Saliva was then collected for 15 min. After 15 min., the swab was weighed and the difference in its weight was used to calculate the antisecretory potency of the antagonists. The data was fit to normal isotherms and ID[0334] 50 values were extracted.
    • Example 6 In Vivo Bladder Assay
  • Male Sprague-Dawley rats weighing 250-300 g were anesthetized with urethane (1.3 g/kg, i.p.), inactin (25 mg/kg, i.p.), and xylazine (4 mg, i.p.). The jugular (or femoral) vein was isolated and ligated and a small incision was made in the vein distal to the ligation. A catheter (micro-Renathane tubing (0.014 mm ID×0.033 mm OD) filled with saline was inserted into the vein and secured into place with suture thread. The trachea was isolated and placed in a small hole between two of the rings. Tubing (1.57 mm ID×2.08 mm OD) was inserted into the trachea and tied into place with suture thread. The incision was closed leaving the tubing exposed. The tracheotomy was to prevent the animal from asphyxiating on his own saliva following oxotremorine administration. The stomach was shaved and then cleaned with ethanol. A midline sagital incision was made in the skin and muscle layers of the lower stomach. The bladder was exposed and the saline filled cannula (22-gauge needle attached to a pressure transducer with PE 90 tubing) was inserted into the apex of the bladder to the most distal part of the bladder. The bladder was placed back into the peritoneal cavity. The bladder was emptied manually by disconnecting the cannula and allowing the contents to flow out until the bladder was approximately 1 cm in diameter. The incision was closed with suture thread, first the muscle layer, then the skin in order to keep the bladder moist and warm. The exposed portion of the cannula to the skin surface was sutured to hold it in place. After 15 min. oxotremorine (0.3 mg/kg, SC, baseweight) was injected. After 10 min., (or until baseline stabilized) a test compound or a reference standard was injected with a dose equivalent to 0.005-0.01 mg/kg, IV, baseweight of atropine that produced a 30-70% decrease in intraluminal pressure. After 5 min., a high dose of atropine 0.1 mg/kg was injected, i.v., to establish the true 100% inhibition point. [0335]
  • For data analysis, the oxotremorine response (zero inhibition) was determined by measuring the mean pressure 1 minute prior to the antagonist injection. Then, to assess antagonist inhibition, mean pressure was mesured beginning at 1 minute and ending 2 minutes after antagonist administration. If the pressure had not leveled off after 1 minute, a wait was initiated until it was stable and then a 1-minute sample of the mean was taken. Lastly, to determine the true 100% inhibition point, the mean pressure was measured beginning 1 minutes and ending 2 minutes after the high dose atropine challenge. The percent inhibition by the antagonist can be determined by the ratio of the decrease from the zero to 100% values. [0336]
  • The formula is: oxotremorine mean−treatment mean*100 oxotremorine mean−atropine mean. [0337]
  • Additionally, the activity of a compound of the invention on other tissues can be determined using screening protocols that are known in the art. For example, an assessment of increased locomotor activity (assay for CNS penetration) can be carried out as described by Sipos M L, et al., (1999) [0338] Psychopharmacology 147(3):250-256; an assessment of the effects of a compound on gastrointestinal motility can be carried out as described by Macht D I, and Barba-Gose J (1931) J Am Pharm Assoc 20:558-564; an assessment of the effects of a compound on pupil diameter (mydriasis) can be carried out as described by Parry M, Heathcote B V (1982) Life Sci 31:1465-1471; and an assessment of a compounds effects on urinary bladder in dog can be carried out as described by Newgreen D T, et al. (1996) J Urol 155:600A.
  • Preferred compounds of the invention may display selectivity for one or more tissues over other tissues. For example, compounds of the invention that are useful for treating urinary incontinence may show higher activity in the assay of Example 6 than in the assay of Example 5. [0339]
  • Preferred compounds useful for treating urinary incontinence and irritable bowel syndrome have greater antagonist activity at the M[0340] 2 receptor than at the M3 receptor or the other muscarinic receptors.
  • Preferred compounds useful for treating unwanted salivation have greater antagonist activity at the M[0341] 3 receptor than at the M2 receptor or the other muscarinic receptors.
  • The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. [0342]
  • All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted. [0343]

Claims (51)

What is claimed is:
1. A compound of Formula (I):
L1—X—L2   (I)
wherein:
L1 is a group of formula (a):
Figure US20040054187A1-20040318-C00590
wherein:
A is an aryl or a heteroaryl ring;
B″ is —NRa— wherein Ra is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
R1 is hydrogen or alkyl;
R2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii):
Figure US20040054187A1-20040318-C00591
wherein:
- - - is an optional double bond;
n1 is an integer of from 1 to 4;
n2 is an integer of from 1 to 3;
V is —CH—, —O—, —S(O)n3— (where n3 is an integer of from 0 to 2), or —NR4— (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
“Het” is a heteroaryl ring which optionally attaches (a) to a linker;
R3 is hydrogen, alkyl, halo, amino, substituted amino, —ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
R5 is hydrogen, alkyl, halo, amino, substituted amino, —ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
K is a bond or an alkylene group;
K″ is a bond, —C(O)—, —S(O)n4— (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and
B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;
provided that at least one of the R5, R6, R7, R8, “Het”, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
X is a linker; and
L2 is an organic group comprising at least one primary, secondary, or tertiary amine;
or a pharmaceutically acceptable salt; or prodrug thereof.
2. The compound of claim 1 wherein L2 is a group selected from a group consisting of:
(i) a group of formula (b):
Figure US20040054187A1-20040318-C00592
wherein:
D″ is alkylene;
D is —NR31R32, —N+(R33R34R35) or —OR32 where R31, R33, and R34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R32 and R35 represent a covalent bond attaching (b) to a linker;
R27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R29 and R30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or
one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group;
(ii) a group of formula (c):
Figure US20040054187A1-20040318-C00593
wherein:
n11 is an integer of from 1 to 7;
n12 is 0 to 7;
F is —NR40—, —O—, —S—, or —CHR41— (wherein R40 and R41 are, independently of each other, hydrogen, alkyl, or substituted alkyl);
F″ is a covalent bond, —OR43, —NR42R43, or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and
R38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R38 and R43 attaches (c) to a linker;
R39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and
(iii) a group of formula (d) or (e):
Figure US20040054187A1-20040318-C00594
wherein:
R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;
R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR50 where R50 is alkyl; or
R46 and R47 together with the nitrogen atom to which they are attached form heterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
R48 is a covalent bond that attaches the (d) to a linker; and
R49 is alkyl.
3. The compound of claim 1 or 2 wherein A is phenyl or pyridyl.
4. The compound of claim 1 or 2 wherein B″ is —NH—.
5. The compound of claim 1 or 2 wherein R1 is hydrogen, methyl, or ethyl.
6. The compound of claim 1 or 2 wherein R2 is pyrrolyl, pyridinyl, or imidazolyl.
7. The compound of claim 1 or 2 wherein R2 is phenyl.
8. The compound of claim 1 or 2 wherein K is a bond or a methylene group.
9. The compound of claim 1 or 2 wherein K″ is a bond.
10. The compound of claim 1 or 2 wherein B is a heterocycloamino group which attaches (a) to a linker.
11. The compound of claim 1 or 2 wherein B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker.
12. The compound of claim 1 or 2 wherein B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.
13. The compound of claim 1 or 2 wherein B is piperidin-4-yl, piperidin-3-yl, or 4-methylpiperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.
14. The compound of claim 2 wherein: R46 is alkyl or substituted alkyl; R47 is alkyl, substituted alkyl, or heterocycle; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle.
15. The compound of claim 1 or 2 wherein L2 has any one of the formula A1-A590 shown hereinabove.
16. The compound of claim 1 or 2 wherein L2 is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.
17. The compound of claim 1 wherein L1 is:
Figure US20040054187A1-20040318-C00595
18. The compound of claim 18 wherein the piperidino nitrogen of L1 is bonded to X.
19. The compound of claim 1 or 2 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
20. The compound of claim 1 or 2 wherein X is a group of formula:
—Xa—Z—(Ya—Z)m—Yb—Z—Xa—
wherein
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —NR′—C(Xa)═N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)nCR′R″—, —S(O)n—NR′—, —NR′—S(O)n—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; provided at least one of Xa, Ya, Yb or Z is not a covalent bond.
21. The compound of claim 1 or 2 wherein X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl.
22. The compound of claim 1 or 2 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
23. The compound of claim 1 or 2 wherein X has the following formula:
Figure US20040054187A1-20040318-C00596
wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.
24. The compound of claim 1 or 2 wherein X has one of the following the formula:
Figure US20040054187A1-20040318-C00597
25. The compound of claim 2 which is a compound of Formula (Ia):
Figure US20040054187A1-20040318-C00598
or a pharmaceutically acceptable salt or prodrug thereof.
26. The compound of claim 25 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
27. The compound of claim 25 wherein X is a group of formula:
—Xa—Z—(Ya—Z)m—Yb—Z—Xa—
wherein
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —NR′—C(Xa)═N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)nCR′R″—, —S(O)n—NR′—, —NR′—S(O)n—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; provided at least one of Xa, Ya, Yb or Z is not a covalent bond.
28. The compound of claim 25 wherein X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl.
29. The compound of claim 25 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
30. The compound of claim 25 wherein X has the following formula:
Figure US20040054187A1-20040318-C00599
wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.
31. The compound of claim 25 wherein X has one of the following the formula:
Figure US20040054187A1-20040318-C00600
32. The compound of claim 1 which is a compound of formula (IVa):
Figure US20040054187A1-20040318-C00601
wherein X, an L2 are defined as in claim 1; or a pharmaceutically acceptable salt or prodrug thereof.
33. The compound of claim 32 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
34. The compound of claim 32 wherein X is a group of formula:
—Xa—Z—(Ya—Z)m—Yb—Z—Xa—
wherein
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR—or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —NR′—C(Xa)═N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)nCR′R″—, —S(O)n—NR′—, —NR′—S(O)n—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; provided at least one of Xa, Ya, Yb or Z is not a covalent bond.
35. The compound of claim 32 wherein X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl.
36. The compound of claim 32 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
37. The compound of claim 32 wherein X has the following formula:
Figure US20040054187A1-20040318-C00602
wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.
38. The compound of claim 32 wherein X has one of the following the formula:
Figure US20040054187A1-20040318-C00603
39. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
40. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and R47 is alkyl, substituted alkyl, acyl, or —COOR50.
41. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NRaRb, wherein Ra and Rb may be the same or different and and are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclic.
42. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl —SO2-heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
43. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R46 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
44. The compound of claim 1 wherein R46 and R47 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
45. The compound of claim 1 wherein R46 and R47 together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).
46. Compound number 1-643 as described in Table A, Table B, Table C, Table D, Table E, or Table F; or a pharmaceutically acceptable salt or prodrug thereof.
47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or 2.
48. A method of treating a disease mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 or 2.
49. The method of claim 48 wherein the disease is urinary incontinence, chronic pulmonary obstructive disease, asthma, hyper-salivation, a cognitive disorder, blurred vision, or irritable bowel syndrome.
50. A compound of formula L1—H wherein L1 has the values defined in claim 1; or a salt thereof
51. The compound of claim 50 which is
Figure US20040054187A1-20040318-C00604
or a salt thereof.
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