| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 31.12.02 |
| PATENT TITLE |
Benzocycloalkylenylamine derivatives as muscarinic receptor antagonists |
| PATENT ABSTRACT |
This invention relates to compounds which are generally muscarinic M2/M3 receptor antagonists and which are represented by Formula I: ##STR1## wherein X, Y, and Z are O, S, or NR.sup.4, and the other substituents are as defined in the specification; and prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | May 22, 2001 |
| PATENT REFERENCES CITED |
Homan et al., "Structural Analogues of 5-Ome-BPAT: Synthesis and Interactions with Dopamine D.sub.2, D.sub.3, and Serotonin 5-HT.sub.1A Receptors", Bioorg. Med. Chem., (1999), pp. 1111-1121, vol. 7(6). Glennon et al, "N-(Phthalimidoalkyl) Derivatives of Serotonergic Agents: A Common Interaction at 5-HT.sub.1A Serotonin Binding Sites?", J.Med. Chem., (1989), pp. 1921-1926, vol. 32. Ehlert, et al., "Subtypes of the Muscarinic Receptor in Smooth Muscle", Life Sciences, (Minireview), (1997), pp. 1729-1740, vol. 61, No. 18. Hedge, et al., "Muscarinic Receptor Subtypes Modulating Smooth Muscle Contractility in the Urinary Bladder", Life Sciences, (1999), pp. 419-428, 64, Nos. 6/7. Eglen, et al., "Muscarinic acetylcholine receptor subtypes in smooth muscle", Trends. Pharmacol. Sci., (1994), pp. 114-119, vol. 15. Eglen, et al, "Muscarinic receptor subtypes and smooth muscule function", Pharmacol. Rev., (1996), pp. 531-565, vol. 48, No. 4. Nilvebrant, et al., "Tolterodine--A new Bladder Selective Muscarinic Receptor Antagonist: Preclinical Pharmacological and Clinical Data", Life Sciences, (1997), pp. 1129-1136, vol. 60. Alabaster, "Discovery & Development of Selective M.sub.3 Antagonists for Clinical Use", Life Sciences, (1997), pp. 1053-1060, vol. 60, Nos. 13/14. Osayu, et al, "Urinary Bladder-selective Action of the New Antimuscarinic Compound Vamicamide", Drug Res., (1994) , pp. 1242-1249, vol. 44(II), No. 11. Homma, et al, "Randomized Double-Blind Study to Compare Clinical Efficacy of Temiverine and Propiverine for Unstable Bladder and Detrusor Hyperreflexia", Neurology and Urodynamics,--Abstract, (1997), pp. 345-346, vol. 16. Eglen and Hegde, "Selective modulation of muscarinic receptor subtypes: therapeutic potential", Emerging Drugs,--Chapter 4, (1998), pp. 67-79, vol. 3, Ashley Publications. Eglen, et al, "Muscarinic receptor ligands and their therapeutic potential", Curr. Opin. Chem. Biol. (1999), pp. 426-432, vol. 3, Elsevier Science. Caulfield, et al, "International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors", Pharmacological Reviews, (1998), pp. 279-290, vol. 50(2). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound Formula I ##STR22## wherein: R.sup.1, and R.sup.2 are independently in each occurrence hydrogen, halogen, (C.sub.1-6)-alkyl, --OR', --SR', --NR'R", --SOR', --SO.sub.2 R', --COOR', --OCOR', --OCONR'R", --OSO.sub.2 R', --OSO.sub.2 NR'R"; --NR'SO.sub.2 R", --NR'COR", --SO.sub.2 NR'R", --SO.sub.2 (CH.sub.2).sub.1-3 CONR'R", --CONR'R", cyano, haloalkyl, or nitro; wherein R' and R" are independently in each occurrence hydrogen, (C.sub.1-6)-alkyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C.sub.1-3)-alkyl, heteroaryl-(C.sub.1-3)-alkyl, heterocyclyl-(C.sub.1-3)- alkyl, cycloalkylalkyl, cycloalkyl, or R' and R" together with the nitrogen they are attached may also form a 5- to 7-membered ring, optionally incorporating one additional ring heteroatom chosen from N, O or S(O).sub.0-2 ; R.sup.3 is independently in each occurrence (C.sub.1-6) alkyl, (C.sub.1-6) alkenyl, (C.sub.1-6) alkynyl, or cycloalkyl; or Y is N--R.sup.4 and X and Z are CH.sub.2, or Z is N--R.sup.4 and X and Y are CH.sub.2 ; R.sup.4 is hydrogen, (C.sub.1-6)-alkyl, haloalkyl, aryl(C.sub.1-6)alkyl, heteroaryl(C.sub.1-6)alkyl, --(C.sub.1-6)--CR'R'R', --COOR', --SO.sub.2 R', --C(O)R', --SO.sub.2 (CH.sub.2).sub.0-3 NR'R", --CONR'R", or --PO(OR').sub.2, wherein R' and R" are as defined above; substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol; heterocyclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N,O or S(O).sub.0-2, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, arylaminocarbonyl, alkylcarbonylamino, or arylcarbonylamino; heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulfur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonlamino and arylcarbonylamino; cycloalkyl means a monovalent saturated carbocyclic radical consisting of one or two rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino; p is an integer from 1 to 3 inclusive; m is 2; n is an integer from 1 to 6 inclusive; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. 2. The compound of claim 1, wherein p is 2. 3. The compound of claim 1, wherein n is 3. 4. The compound of claim 2, wherein n is 3. 5. The compound of claim 2, wherein R.sup.4 is hydrogen. 6. The compound of claim 4, wherein one of Y or Z is NH, and the other is CH.sub.2. 7. The compound of claim 6, wherein Y is NH, and X and Z are CH.sub.2. 8. The compound of claim 6, wherein Z is NH, and X and Y are CH.sub.2. 9. The compound of claim 1 selected from group consisting of 3,5- dimethyl-isoxazole-4-sulfonic acid 7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}- 5,6,7,8-tetrahydro-naphthalen-2-yl ester; 4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7- methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diaz epan-2-one; 4-}4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,4]diazepan-5-one; 4-{-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl- amino]-pentyl}-[1,4]diazepan-5-one; 1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2- y;)-propyl-amino]-butyl}-[1,4]diazepan-2-one; and 1-{4-[(7-bromo-1,2,3,4-tetrahyro- naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one; or an individual isomer, a racemic or non-racemic mixture of isomers, or pharmaceutically acceptable salt or solvate thereof. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in admixture with a pharmaceutically acceptable carrier. 11. A method of treating a disease state associated with smooth muscle disorders selected from diseases of the genitourinary or gastrointestinal tract, or a disease state comprising allergies, asthma, chronic obstructive pulmonary disease or pulmonary fibrosis by administering to a patient a therapeutically effective amount of a compound of claim 1. 12. The method of treatment of claim 11, wherein the disease state associated with the genitourinary tract comprises overactive bladder, detrusor hyperactivity, urgency, frequency, reduced bladder capacity, incontinence episodes, changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, outlet obstruction, outlet insuffciency, pelvic hypersensitivity, idiopathic conditions, or detrusor instability. 13. The method of treatment of claim 11, wherein the disease state comprises allergies asthma, chronic obstructive pulmonary disease or pulmonary fibrosis. 14. The method of treatment of claim 11, wherein the disease state associated with gastrointestinal tract disorders comprises irritable bowel syndrome, diverticular disease, achalasia, gastrointestinal hypermotility disorders, or diarrhea. 15. A process for preparing a compound as claimed in claim 1 which process comprises reacting a compound having a general formula ##STR23## with a compound of general formula ##STR24## to provide a compound of Formula I ##STR25## wherein R.sup.1, R.sup.2, R.sup.3, p, m, n, X, Y, and Z are as defined in claim 1. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to benzocycloalkylenylamine derivatives, associated pharmaceutically acceptable salts, or hydrates thereof, and associated pharmaceutical compositions and methods for use as M2/M3 selective muscarinic receptor antagonists. BACKGROUND OF THE INVENTION Acetylcholine (Ach) is the principal transmitter of the parasympathetic nervous system. The physiological actions of Ach are mediated by activation of either nicotinic or muscarinic receptors. Both of these receptor classes are heterogeneous: e.g., the muscarinic receptor family comprises five subtypes (M.sub.1, M.sub.2, M.sub.3, M.sub.4, and M.sub.5) each encoded by distinct genes and possessing unique pharmacology and distribution. Almost all smooth muscle tissues express both muscarinic M2 and M3 receptors, both of which have a functional role. M2 receptors outnumber M3 receptors by a proportion of approximately 4 to 1. Generally, M3 receptors mediate the direct contractile effects of acetylcholine in the vast majority of smooth muscle tissues. M2 receptors, on the other hand, cause smooth muscle contraction indirectly by inhibiting sympathetically (.beta.-adrenoreceptor)-mediated relaxation. Compounds that act as antagonists of muscarinic receptors have been used to treat several disease states associated with improper smooth muscle function. Until recently, most of these compounds have been non-selective for the various muscarinic receptor subtypes, leading to unpleasant anti-cholinergic side-effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side-effects is dry-mouth resulting from muscarinic receptor blockade in the salivary gland. Recently developed M2 or M3 specific antagonists have been shown to have reduced side effects. Evidence suggests that concurrent blockade of M2 and M3 receptors could be therapeutically effective in the treatment of disease states associated with smooth muscle disorders. Few M2/M3 selective antagonists have been developed. The present invention fills this need by providing these types of antagonists useful in the treatment of disease states associated with improper smooth muscle function. SUMMARY OF THE INVENTION This invention relates to compounds comprising Formula I: ##STR2## wherein: R.sup.1, and R.sup.2 are independently in each occurrence hydrogen, halogen, (C.sub.1-6)-alkyl, --OR', --SR', --NR'R", --SOR', --SO.sub.2 R', --COOR', --OCOR', --OCONR'R", --OCONR'R", --OSO.sub.2 R', --OSO.sub.2 NR'R"; --NR'SO.sub.2 R", --NR'COR", --SO.sub.2 NR'R", --SO.sub.2 (CH.sub.2).sub.1-3 CONR'R", --CONR'R", --NR'CONR'R", cyano, haloalkyl, or nitro; R' and R" are independently in each occurrence hydrogen, (C.sub.1-6)-alkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, aryl-(C.sub.1-3)-alkyl, heteroaryl-(C.sub.1-3)-alkyl, heterocyclyl-(C.sub.1-3)-alkyl, cycloalkylalkyl, cycloalkyl, or R' and R" together with the nitrogen they are attached may also form a 5- to 7- membered ring, optionally incorporating one additional ring heteroatom chosen from N, O or S(O).sub.0-2 ; R.sup.3 is independently in each occurrence (C.sub.1-6) alkyl, (C.sub.1-6) alkenyl, (C.sub.1-6) alkynyl, or cycloalkyl; one of X, Y or Z is independently S, O, or N--R.sup.4, the others are CH.sub.2 ; R.sup.4 is hydrogen, (C.sub.1-6)-alkyl, haloalkyl, aryl(C.sub.1-6)alkyl, heteroaryl(C.sub.1-6)alkyl, --(C.sub.1-6)--CR'R'R', --COOR', --SO.sub.2 R', --C(O)R', --SO.sub.2 (CH.sub.2).sub.0-3 NR'R", --CONR'R", or --PO(OR').sub.2, where R' and R" are as defined above; m is an integer from 0 to 3 inclusive; n is an integer from 1 to 6 inclusive; p is an integer from 1 to 3 inclusive; and prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. In a preferred embodiment p is 2. In another preferred embodiment p is 2, and one of X, Y or Z is NR.sup.4 and the others are CH.sub.2 ; in another embodiment p is 2, and one of X, Y or Z is NR.sup.4 and the others are CH.sub.2, wherein R.sup.4 is hydrogen. In another preferred embodiment, p is 2 and m is 1; in another preferred embodiment p is 2, m is 1 and Y is NR.sup.4 and the others are CH.sub.2 and in another preferred embodiment p is 2, m is 1 and one of X is NH and the others are CH.sub.2 ; In another preferred embodiment, p is 2, m is 2; in another preferred embodiment, p is 2, m is 2, and one of X, Y or Z is NR.sup.4 and the others are CH.sub.2, and in another preferred embodiment p is 2, m is 2, and one of X is NH and the others are CH.sub.2. In another embodiment n is 3 and p is 2, in another embodiment n is 3, and one of X, Y or Z is NR.sup.4 and the others are CH.sub.2 ; in another embodiment n is 3, p is 2 and one of X, Y, or Z is NR.sup.4 and the others are CH.sub.2 ' in another embodiment n is 3, p is 2 and one of X, Y, or Z is NH and the others are CH.sub.2. In another preferred embodiment n is 3, p is 2, m is 2 and one of X, Y, or Z is NR.sup.4 and the others are CH.sub.2 ; and in another preferred embodiment n is 3, p is 2, m is 2, X is NH, and Y and Z are CH.sub.2. In another preferred embodiment n is 3, p is 2, m is 2, Y is NH and X and Z are CH.sub.2. In another preferred embodiment n is 3, p is 2, m is 2, Z is NH and X and Y are CH.sub.2. In another embodiment n is 3 and one of X, Y, or Z is NR.sup.4 and the others are CH.sub.2. In another preferred embodiment p is 2, m is 2, n is 3, one of X, Y or Z is O and the others are CH.sub.2. In a preferred embodiment, the invention further relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula I, or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier. In a more preferred embodiment, the pharmaceutical compositions are suitable for administration to a subject having a disease state which is alleviated by treatment with a muscarinic M2/M3 receptor antagonist. In another aspect, the invention relates to methods for treating a subject having a disease state that is alleviated by treatment with a muscarinic M2/M3 receptor antagonist, which comprises administering to such a subject a therapeutically effective amount of at least a compound of Formula I. In a preferred embodiment, the subject has a disease state comprising smooth muscle disorders; preferably genitourinary tract disorders, respiratory tract disorders, gastrointestinal tract disorders; more preferably genitourinary tract disorders such as overactive bladder or detrusor hyperactivity and its symptoms, such as the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficiency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like. In another preferred embodiment, the disease comprises respiratory tract disorders such as allergies and asthma. In another preferred embodiment, the disease state comprises gastrointestinal disorders. In another aspect, the invention relates to a process for preparing a compound of Formula I, which process comprises reacting a compound having a general formula ##STR3## with a compound of general formula ##STR4## to provide a compound of Formula I: ##STR5## |
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