WO1996014845A1 - Nk-1 receptor antagonists for the treatment of eye disorders - Google Patents

Nk-1 receptor antagonists for the treatment of eye disorders Download PDF

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Publication number
WO1996014845A1
WO1996014845A1 PCT/IB1995/000811 IB9500811W WO9614845A1 WO 1996014845 A1 WO1996014845 A1 WO 1996014845A1 IB 9500811 W IB9500811 W IB 9500811W WO 9614845 A1 WO9614845 A1 WO 9614845A1
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Prior art keywords
alkyl
phenyl
optionally
substituted
carbon
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PCT/IB1995/000811
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French (fr)
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Hans-Jurgen Ernst Hess
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Pfizer Inc.
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Priority to MX9703483A priority Critical patent/MX9703483A/en
Priority to EP95931373A priority patent/EP0790825A1/en
Priority to JP8515865A priority patent/JPH10508837A/en
Publication of WO1996014845A1 publication Critical patent/WO1996014845A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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

Definitions

  • the present invention relates to a method of treating or preventing a disorder of the eye selected from glaucoma ocular hypertension, miosis, excess lacrimation, hyperemia and breakdown of the blood aqueous barrier in mammals, including humans, using an NK-1 antagonist. It also relates to a method of treating or preventing such disorders in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, pyrrolidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds that are substance P receptor antagonists.
  • This invention relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to such mammal an amount of a substance P receptor antagonist that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to such mammal an amount of a NK-1 receptor antagonist that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, and ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
  • A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR 2 R 3 is attached to a carbon atom of ring system A;
  • AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR 2 R 3 is attached to a carbon atom of AA;
  • AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the -CH 2 PR 3 sidechain is attached to a carbon atom of ring AAA;
  • P is NR 2 , O, S, SO or SO 2 ;
  • Q is SO 2 , NH, or wherein the point of attachment of said to
  • ring AAA is the nitrogen atom and the point of attachment to
  • X 5 is the sulfur atom
  • W 1 is hydrogen, halo or (C 1 -C 6 ) alkyl, S-(C 1 -C 3 ) alkyl, halo or (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • W 2 is hydrogen, (C 1 -C 6 ) alkyl, S-(C 1 -C 3 ) alkyl, halo or (C 1 - C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • W is hydrogen, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, -S(O) v -(C 1 -C 6 ) alkyl wherein v is zero, one or two, halo or (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • X 1 is hydrogen, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms or (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms;
  • X 2 and X 3 are independently selected from hydrogen, halo, nitro, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C 1 -C 6 )- alkylamino, di-(C 1 -C 6 )alkylamino, , (C 1 -C 6 )- , hydroxy(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy(C 1 - C 4 )alkyl, and ;
  • X 5 is a four to six membered heterocyclic ring containing from one to three heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms and halo;
  • heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C 1 -C 6 ) alkyl optionally substituted with from one to three
  • R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 1 is selected from amino, (C 1 -C 6 ) alkylamino, di-(C 1 -C 6 )alkylamino, -S(O) v -(C 1 -C 10 )-alkyl wherein v is zero, one or two, -S(O) v -aryl wherein v is zero, one or two, -O-aryl, -SO 2 NR 4 R 5 wherein each of R 4 and R 5 is, independently, (C 1 - C 6 )alkyl, or R 4 and R 5 , together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, , ,
  • alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO 2 -(C 1 -C 10 )alkyl) 2 and ; and wherein the aryl moieties of said -S(O) v -aryl, -O-aryl and are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from o
  • R 1 is a group having the formula
  • a is 0, 1 or 2 and the asteris), represents a position meta to the R 2 R 3 NCH 2 side chain;
  • -N(R 4 )- C(C 6 H 5 )-, -CH(C 6 H 5 )-, -C[(C 1 -C 6 ) alkyl]- and -CH[(C 1 -C 6 )alkyl]-;
  • R 4 is (C 1 -C 6 ) alkyl or phenyl
  • R 2 is hydrogen or -CO 2 (C 1 -C 10 ) alkyl
  • R 3 is selected from
  • R 6 and R 10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C 1 -C 3 ) alkoxy-carbonyl;
  • R 7 is selected from (C 3 -C 4 ) branched alkyl, (C 5 -C 6 ) branched alkenyl, (C 5 -C 7 ) cycloalkyl, and the radicals named in the definition of R 6 ;
  • R 8 is hydrogen or (C 1 -C 6 ) alkyl
  • R 9 and R 19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R 9 and R 19 may optionally be substituted with from one to three substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • Y 1 is (CH 2 ) 1 wherein 1 is an integer from one to three, or Y 1 is a group of the formula
  • Z 1 is oxygen, sulfur, amino, (C 1 -C 3 ) alkylamino or (CH 2 ) n wherein n is zero, one or two;
  • x is an integer from zero to four;
  • y is an integer from zero to four;
  • z is an integer from one to six, wherein the ring containing (CH 2 ) z may contain from zero to three double bonds, and one of the carbons of (CH 2 ) z may optionally be replaced by oxygen, sulfur or nitrogen;
  • o is two or three
  • R 11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • X 4 is (CH 2 ) q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH 2 ) q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 14 , and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 15 ;
  • m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m may optionally be substituted with R 17 ;
  • R 12 is a radical selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein the point of attachment on R 12 is a carbon atom unless R 12 is hydrogen, are wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C 2 -C 6 ) alkyl
  • phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
  • R 13 is hydrogen, phenyl or (C 1 -C 6 ) alkyl
  • R 12 and R 13 together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
  • R 16 is , NHCH 2 R 18 , SO 2 R 18 , GR 20 CO 2 H or one of the radicals set forth in any of the definitions of R 12 , R 14 and R 15 ;
  • R 18 is (C 1 -C 6 ) alkyl, hydrogen, phenyl or phenyl (C 1 -C 6 )alkyl;
  • G is selected from the group consisting of CH 2 , nitrogen, oxygen, sulfur and carbonyl;
  • R 20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
  • B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH 2 ) n or (CH 2 ) n+1 may be optionally substituted with (C 1 -C 6 ) alkyl or (C 2 -C 6 ) spiroalkyl, and either any two of the carbon atoms of said (CH 2 ) n and (CH 2 ) n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbons of said (CH 2 ) n and (CH 2 ) n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C 3 -C 5 ) fused carbocyclic ring;
  • each of R 14 and R ⁇ s is independently selected from hydrogen, fluoro, (C 1 -C 6 ) alkyl, hydroxy-(C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy- (C 1 -C 6 ) alkyl, or R 14 and R 15 , together with the carbon to which they are attached, form a (C 3 -C 6 ) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R 12 and R 13 cannot both be hydrogen; (e) when R 14 or R 15 is attached to a carbon atom of X 4 or (CH 2 ) y that
  • the fused bicyclic nucleus of compounds of the formula Ib to which W and the -CN 2 NR 2 R 3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (1) through (47A) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • R 3 is a group of the formula VII or VIII, "a cis configuration", as used herein, means that the non-hydrogen substituent at position "3" is cis to R 12 ).
  • R 3 is a group of the formula III, VII or IX;
  • R 2 is hydrogen;
  • A is phenyl or indolinyl;
  • W is (C 1 -C 3 ) alkoxy optionally substituted with from one to five fluorine atoms; and
  • R is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, and R may optionally be substituted with one or two (C 1 -C 3 ) alkyl moieties.
  • R 3 is a group of the formula III and R 9 is benzhydryl
  • R 3 is a group of the formula VII, R 12 is phenyl, each of R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero and X 4 is -(CH 2 ) 3 -
  • R 3 is a group of the formula IX, r is two and R 19 is benzhydryl.
  • R 3 is a group of the formula III wherein the substituents at positions "2" and “3" of the nitrogen containing ring are in the cis configuration, R 9 is benzhydryl and A is pheryl; or (b) R 3 is a group of the formula VII wherein R 12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, A is phenyl, R 12 is phenyl.
  • each of R 2 , R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero, W methoxy or isopropoxy, X 4 is -(CH 2 ) 3 - and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl or thiadiazolyl.
  • a compound of the formula la wherein R 3 is a group of the formula VII, each of R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero, X 4 is -(CH 2 ) 3 -, A is phenyl, W is methoxy, and R is selected from thiazolyl, imidazolyl, thiadiazolyl and isoxazolyl.
  • a compound of the formula Ic wherein R 3 is a group of the formula II, III, VII or IX; R 2 is hydrogen; ring AA is phenyl or indolinyl; W 1 is (C 1 -C 3 )alkoxy optionally substituted with from one to three fluorine atoms; and R 1 is
  • (C 1 -C 10 ) alkyl wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO 2 -(C 1 -C 10 )alkyl) 2 or
  • aryl is phenyl or benzyl and may optionally be substituted with from one to three substituents independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy and halo.
  • R 6 and R 7 is phenyl
  • R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero, X 4 is -(CH 2 ) 2 - or
  • R 1 is selected from S(O) v -(C 1 -C 10 ) alkyl wherein v is zero, one or two, and , and
  • ring AA is phenyl
  • W 1 is selected from isopropoxy, OCF 3 , OCH 3 , OCHF 2 and OCH 2 CF 3
  • R 1 is selected from -S(O) v - (C 1 -C 10 ) alkyl wherein v is zero, one or two, and (C 1 -C 10 )alkyl-N-SO 2 -(C 1 -C 10 ) alkyl.
  • a compound of the formula Ic wherein R' is a group of the formula VII, m is zero, each of R 1 , R 2 , R 3 and R 17 is hydrogen, R 12 is phenyl, R 14 is , ring AA is phenyl, W 1 is (C 1 -C 3 ) alkoxy and R 1 is selected from (C 1 -C 5 )alkyl, -SCH 3 , SO 2 CH 3 , SOCH 3 , (C 1 -C 6 ) alkylamino and di-(C 1 -C 6 )alkyl-amino.
  • R 6 , R 10 , R 11 and R 13 are phenyl
  • R 8 is hydrogen
  • R 9 is phenyl optionally substituted with chlorine, fluorine, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms or (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms
  • m is O and n is 3 or 4.
  • R 3 is a group of the formula VIII wherein y is zero, x is zero or one, z is three or four, m is zero and R 12 is phenyl or substituted phenyl.
  • R 3 is a group of the formula VII, R 6 , R 14 , R 13 R 16 and R 15 are hydrogen, R 12 is phenyl, X 1 is 2-methoxy, X 2 and X 3 are independently selected from hydrogen, chlorine, fluorine, methyl, (C 1 -C 6 ) alkoxy and trifluoromethane, m is 0 and q is 3 or 4.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human comprising administering to said mammal an amount of a compound having the formula
  • W is Y or X(CH 2 ) n ;
  • Y is optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl or optionally substituted (C 3 -C 8 )cycloalkyl;
  • X is optionally substituted (C 1 -C 6 ) alkoxy, hydroxy, CONR 1 R 2 , CO 2 R 1 , CHR 1 OR 2 , CHR 1 NR 2 R 3 , COR 1 , CONR 1 OR 2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
  • Ar 1 , Ar 2 and Ar 3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl. phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and R 1 , R 2 and R 3 are independently selected from hydrogen, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazoly
  • substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl and trifluoromethoxy;
  • substituents on the foregoing substituted (C 1 -C 5 ) heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C 1 -C 4 ) alkyl when attached to a ring sulfur atom, and are independently selected from oxygen and (C 1 -C 4 ) alkyl when attached to a ring nitrogen atom;
  • substituents on said substituted Ar 1 groups are independently selected from (C 1 -C 6 ) alkyl optionally substituted with from one to three halo groups, (C 1 -C 6 ) alkoxy optionally substituted with from one to three halo groups, (C 1 -C 6 )alkylsulfinyl, (C 2 -C 6 ) alkenyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, and di-(C 1 -C 6 ) alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C 1 -C 6 )alkylsulfonyl, or (C 1 -C 6 )alkylsulfinyl group;
  • substituents on said substituted Ar 2 and Ar 3 groups are independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfinyl, di-(C 1 -C 4 )alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C 1 -C 4 ) alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (48) through (54) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (48) through (54) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • a compound as defined in paragraphs (48) through (54) below or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing
  • a compound of the formula X that is selected from the group consisting of:
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma and ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula
  • R 1 is selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C 2 -C 6 ) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo,
  • R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C 3 -C 7 ) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine
  • R 5 and R 6 is hydrogen and the other is selected from hydroxymethyl, hydrogen, (C 1 -C 3 ) alky l, (C 1 -C 8 )acyloxy- (C 1 -C 3 ) alkyl, (C 1 -C 8 )alkoxymethyl and benzyloxymethyl;
  • R 7 and R 8 are independently selected from hydrogen, (C 1 - C 3 ) alkyl and phenyl;
  • R 9 is selected from methyl, hydroxymethyl, R 14 R 15 NCO 2 CH 2 -, R 16 OCO 2 CH 2 -, (C 1 -C 4 ) alkyl-CO 2 CH 2 -, -CONR 17 R 18 , R 17 R 18 NCO 2 -, R 19 OCO 2 -, C 6 H 5 CH 2 CO 2 CH 2 -, C 6 H 5 CO 2 CH 2 -, (C 1 -C 4 ) alkyl- CH(OH)-, C 6 H 5 CH(OH)-, C 6 H 5 CH 2 CH(OH)-, CH 2 halo, R 20 SO 2 OCH 2 , -CO 2 R 16 and R 21 CO 2 -;
  • R 10 and R 11 are independently selected from hydrogen, (C 1 - C 3 ) alkyl and phenyl;
  • R 12 is hydrogen, benzyl or a group of the formula
  • m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH 2 ) m may optionally be substituted with R 23 ;
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 24 are independently selected from hydrogen, (C 1 -C 3 )alkyl and phenyl;
  • R 22 and R 23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy (C 1 -C 6 ) alkyl, (C 1 - C 6 )alkylamino, di-(C 1 -C 6 ) alkylamino, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )-
  • phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
  • R 9 together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R 7 is attached and the carbon to which R 5 and R 6 are attached form a second pyrrolidine ring; with the proviso that when R 9 , together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R 7 is attached and the carbon to which R 5 and R 6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R 12 is absent or R 12 is present and the nitrogen of the second pyrrolidine ring is positively charged; or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier and ocular hypertension in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (55) through (59) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • R 1 is diphenylmethyl
  • R 3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents
  • each of R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 is hydrogen
  • R 9 is selected from hydroxymethyl, methoxymethyl, -CO 2 R 16 , -CONR 17 R 18 , R 14 R 15 NCO 2 CH 2 -, R 16 OCO 2 CH 2 -, (C 1 -C 4 )alkyl-CO 2 CH 2 -, C 6 H 5 CH 2 CO 2 CH 2 -, -CH 2 halo and R 20 SO 2 OCH 2 -
  • R 12 is hydrogen or benzyl.
  • R 1 is phenyl
  • R 3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substiuents
  • each of R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 is hydrogen
  • R 9 is selected from hydroxymethyl, methoxymethyl, -CO 2 R 18 , -CONR 17 R 18 , R 14 R 15 NCO 2 CH 2 CH 2 -, R 16 OCO 2 CH 2 -, (C 1 -C 4 ) alkyl-CO 2 CH 2 -, -CH 2 halo
  • R 12 is hydrogen or benzyl.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
  • R 1 is hydrogen, (C 1 -C 8 ) alkyl, a saturated (C 6 -C 10 ) carbocyclic ring system containing two fused rings, a saturated (C 6 -C 10 ) carbocyclic bridged ring system containing o rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 8 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 2 is hydrogen, benzyl or a group of the formula
  • m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH 2 ) m may optionally be substituted with R 9 ;
  • R 8 and R 9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C 1 -C 6 ) alkyl,
  • phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
  • R 1 and R 2 together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
  • R 4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl gr os may optionally be substituted with one or more substituents, and said (C 3 -C 7 ) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from
  • R 3 is hydrogen, (C 3 -C 8 ) cycloalkyl, (C 1 -C 6 ) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, and (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R s is hydrogen, (C 1 -C 6 ) alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 6 is selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C 2 -C 6 ) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo,
  • R 12 is hydrogen, (C 1 -C 3 ) alkyl or phenyl
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (60) through (62) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • R 2 is hydrogen, or R 2 and R 1 , together with the nitrogen to which they are attached, form a monocyclic ring containing five to seven carbon atoms;
  • R 3 is hydrogen, methyl or phenyl;
  • R 5 is hydrogen;
  • R4 is phenyl or indanyl, wherein said phenyl or indanyl may optionally be substituted with from one to three substituents independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C 1 -C 6 ) alkylamino, -C(O)NH-(C 1 -C 8 ) alkyl, (C 1 -C 6 )alkyl-C(O)-, -C(O)-O-(C 1 -C 6 )
  • R 1 is alkyl
  • R 6 is unsubstituted phenyl
  • R 4 is a monosubstituted or disubstituted aryl group that is substituted at the C-2 position with an alkoxy group or substituted at the C-5 position with an alkyl, alkoxy or trihaloalkoxy group, or substituted in such manner at both C-2 and C-5 positions (i.e., with an alkoxy group at the C-2 position and an alkyl, alkoxy or trihaloalkoxy group at the C-5 position), and each of R 2 , R 3 and R 5 is hydrogen.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
  • R 1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
  • R 2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
  • R 3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl, or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (63) through (65) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal. including a human, comprising administering to said mammal an amount of a compound of the formula
  • m is an integer from 0 to 8
  • any one of the carbon-carbon single bonds of (CH 2 ) m wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m may optionally be substituted with R 8 ;
  • w is an integer from 0 to 2;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH 2 ) z may optionally be substituted with R 4 ;
  • R 1 is hydrogen or (C 1 -C 8 ) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
  • R 2 is a group selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benz
  • R 5 is hydrogen, phenyl or (C 1 -C 6 ) alkyl
  • R 2 and R 5 together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
  • R 3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C 3 -C 7 ) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluor
  • R 6 is , NHCH 2 R 9 , NHSO 2 R 9 or one of the groups set forth in any of the definitions of R 2 , and R 4 ;
  • R 9 is (C 1 -C 6 ) alkyl, hydrogen, phenyl or phenyl (C 1 -C 6 ) alkyl;
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (66) through (68) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • R 2 is a radical selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, amino,
  • benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl.
  • R 2 is a group selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, amino,
  • benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma and ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
  • X 1 is C 1 -C 5 alkoxy or halosubstituted (C 1 -C 3 ) alkoxy;
  • X 2 is hydrogen, halogen, (C 1 -C 5 ) alkyl, (C 2 -C 3 ) alkenyl, (C 2 -C 5 )alkynyl, (C 1 -C 5 ) alkoxy, (C 1 -C 5 )alkylthio, (C 1 -C 5 ) alkylsulfinyl, (C 1 -C 5 ) alkylsulfonyl, halosubstituted (C 1 -C 5 ) alkyl, halosubstituted (C 1 -C 5 ) alkoxy, (C 1 -C 5 ) alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C 1 -C 5 ) alkylsulfonylamino (which may be substituted by halogen), (which may be substituted by halogen in the alkylsulfonyl moiety), (C
  • Ar 1 and Ar 2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
  • A is Y-(CH 2 ) m -CH(R 2 )-(CH 2 ) n -NR 1 -;
  • R 1 is hydrogen, (C 1 -C 5 ) alkyl, benzyl or -(CH 2 ) p -Y;
  • R 2 is hydrogen, (C 1 -C 5 ) alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH 2 ) p -Y;
  • Y is -CN, -CH 2 Z or -COZ;
  • Z is hydroxy, amino, (C 1 -C 5 ) alkoxy, (C 1 -C 5 ) alkylamino or dialkylamino having frc ⁇ 1 to 5 carbon atoms in each alkyl moiety;
  • n and p are each, independently, 0, 1, 2 or 3; and R 1 and R 2 may be connected to form a ring;
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
  • R 1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C 1 -C 6 )-alkylamino, di-(C 1 -C 6 ) alkylamino, , , hydroxy(C 1 -C 4 ) alkyl, , , (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, -S(O) v - (C 1 -C 10 )-alkyl wherein v is zero, one or two, -S(O) v -aryl wherein v is zero, one
  • alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO 2 -(C 1 -C 10 )alkyl) 2 and ; and wherein the aryl moieties of said -S(O) v -aryl, -O-aryl and are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy and halo;
  • R 1 is phenyl substituted with a group having the formula
  • a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R;
  • R 2 is selected from (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C 2 -C 6 ) alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituent
  • phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
  • m is an integer from 0 to 8 , and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m may optionally be substituted with R 4 ;
  • R 3 is selected from NHCH 2 R 8 , SO 2 R 8 , AR 9 , CO 2 H and the radicals set forth in the definitions of R 2 , R 6 and R 7 ;
  • A is CH 2 , nitrogen, oxygen, sulfur or carbonyl
  • R 8 is (C 1 -C 6 ) alkyl, hydrogen, phenyl or phenyl (C 1 -C 6 ) alkyl;
  • R 9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
  • B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH 2 ) n and (CH 2 ) n+1 may be optionally substituted with (C 1 -C 6 ) alkyl or (C 2 -C 6 ) spiroalkyl; and either any one pair of the carbon atoms of said (CH 2 ) n and (CH 2 ) n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH 2 ) n and (CH 2 ) n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C 3 -C 5 ) fused carbocyclic ring;
  • X is (CH 2 ) q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH 2 ) q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 6 , and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 7 ;
  • Y is (CH 2 ) z wherein z is zero or one;
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (70)-(75) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
  • Ar 1 and Ar 2 are each independently aryl or substituted aryl
  • R 1 is alkyl having from 1 to 6 carbon atoms
  • R 2 is hydrogen or alkyl having from 1 to 6 carbon atoms; and either X and Y are taken separately and they are each, independently, hydrogen, dialkylphosphoryl having from 2 to 12 carbon atoms, alkyl having from 1 to 6 carbon atoms; or X and Y are taken together and they represent a hydrocarbon chain having 3, 4, or 5 carbon atoms, optionally containing up to 2 double bonds and optionally having 1 or 2 substituents selected from oxo, hydroxy and alkyl having from 1 to 6 carbon atoms;
  • alkylthio is used in formula XVII to mean -SR 4 (R 4 is alkyl) including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio and the like.
  • dialkylphosphoryl is used in formula XVII to mean -P(O) (OR 5 ) (OR 6 ) (R 5 and R 6 are alkyl) including, but not limited to, diethylphosphoryl, ethylmethylphosphoryl and the like.
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (76) - (79) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
  • Ar 1 and Ar 2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
  • X is -CONR 3 R 4 , -CO 2 R 3 , -CH 2 OR 3 , -CH 2 NR 3 R 4 or -CONR 3 OR 4 ;
  • R 1 , R. 3 and R 4 are each, independently, hydrogen or alkyl having 1 to 4 carbon atoms;
  • R 2 is alkyl having 1 to 4 carbon atoms
  • Y is alkylsulfonyl having 1 to 4 carbon atoms, N-alkylN-alkanoylamino (which may be substituted by halogen in the alkanoyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkanoyl moieties, N-alkyl-N-alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkyl sulfonyl moieties, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, halosubstituted alkyl having 1 to 4 carbon atoms, alkylamino having 1 to 4 carbon atoms, alkanoylamino (which may be substituted by halogen) having 1 to 4 carbon atoms
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (80) - (86) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • Y is said alkenyl
  • Y is isopropenyl.
  • (85) A compound as described in paragraph (82) wherein Y is methylsulfonyl, N-acetyl-N-methylamino or N-methyl-N-methylsulfonylamino.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
  • R is C 1 -C 6 alkyl
  • X is C 1 -C 6 alkyl having one or more substituents bonded through a heteroatom
  • Ar 1 and Ar 2 are each, independently, aryl optionally substituted by one C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, cyano, nitro, phenoxy, mono C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, halosubstituted C 1 -C 6 alkyl, or halosubstituted C 1 -C 6 alkoxy;
  • Y is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, Z-(CH 2 ) p -, or W-(CH 2 ) m -CHR 2 -(CH 2 ) n -NR 1 CO- wherein Y is at the 4-, 5- or 6-position on the quinuclidine ring;
  • R 1 is hydrogen, C 1 -C 6 alkyl, benzyl or -(CH 2 ) r -W;
  • R 2 is hydrogen or C 1 -C 6 alkyl which may be substituted by one hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH 2 ) r -W;
  • Z is C 1 -C 6 alkoxy, -CONR 4 R 5 , -CO 2 R 4 , -CHR 4 OR 5 , -CHR 4 NR 5 R 6 , -COR 4 , -CONR 4 OR 5 or optionally substituted aryl;
  • each W is independently cyano, hydroxymethyl, C 2 -C 6 alkoxymethyl, aminomethyl, mono C 1 -C 6 alkylaminomethyl, di C 1 -C 6 alkylaminomethyl, carboxyl, carbamoyl or C 1 -C 6 alkoxycarbonyl;
  • R 4 , R 5 and R 6 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or an optionally substituted aryl or heterocyclic group; p is 0 to 6; and
  • n, r are each, independently, 0 to 3;
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (87) - (91) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
  • X and Y are each hydrogen, halo, C 1 -C 6 alkyl, halosubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl or tri C 1 -C 6 alkylsilyl;
  • Ar 1 and Ar 2 are each aryl optionally substituted by halo;
  • A is -CO- or -(CH 2 )-;
  • Z-A- is at the 2 or 3 position on the quinuclidine ring
  • Z is hydroxy, C 1 -C 6 alkoxy, NR 1 R 2 or W 1 -(CH 2 ) m -CHR 4 -(CH 2 ) n -NR 3 wherein
  • R 1 and R 2 when taken separately, are each hydrogen or C 1 -C 6 alkyl;
  • R 1 and R 2 when taken together with the nitrogen atom to which they are attached, represent piperidino, pyrrolidino, morpholino, thiomorpholino or piperazino;
  • R 3 is hydrogen, C 1 -C 6 alkyl, benzyl or -(CH 2 ) r -W 2 ;
  • R 4 is hydrogen or C 1 -C 6 alkyl which may be substituted by hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxylbenzyl, 3-indolylmethyl or -(CH 2 ) s -W 3 ;
  • R 3 and R 4 when taken together, represent CH 2 or CH 2 CH 2 ;
  • W 1 , W 2 and W 3 are each cyano, hydroxymethyl, C 2 -C 6 alkoxymethyl, aminomethyl, (C 1 -C 6 alkylamino)methyl, (di C 1 -C 6 alkylamino)methyl, carboxyl, (C 1 -C 6 alkyl) carbamoyl, or (di C 1 -C 6 alkyl) carbamoyl, carbamoyl or (C 1 -C 6 alkoxy) carbonyl; and
  • n, r and s are each 0, 1, 2 or 3;
  • alkylthio means -S- alkyl, including but not limited to methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like;
  • alkylsulfonyl means
  • -SO 2 -alkyl including but not limited to methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like;
  • aryl means aromatic radicals including but not limited to phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl and the like. These aryl groups can be substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, cyano, nitro, phenoxy, mono- or di- C 1 -C 6 alkylamino and the like.
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (92) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
  • Y is C 2 -C 4 alkylene
  • Z is a valence bond or C 1 -C 6 alkylene
  • R 1 is phenyl, biphenyl, indanyl, naphthyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, tetrazolyl, quinolyl, phenyl C 1 -C 6 alkyl- or benzhydryl, wherein each of the ring moieties may optionally be substituted by one or more substituents independently selected from halogen, C 1 -C 6 alkyl, halosubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halosubstituted C 1 -C 6 alkoxy;
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 3 is hydrogen, hydroxy, cyano, amino or carboxy; and R 4 represents a group of the formula (II) or (III)
  • X 1 , X 2 and X 3 are each halo, hydrogen, nitro, C 1 -C 6 alkyl, halosubstituted C 1 -C 6 alkoxy, halosubstituted C 1 -C 6 alkoxy, hydroxy, amino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl;
  • Q 1 and Q 2 are each H 2 , oxygen or sulfur;
  • A is valence bond, methylene, oxygen, sulfur or NH;
  • R 5 and R 6 are each hydrogen or C 1 -C 6 alkyl;
  • R 6 is hydrogen, halogen, C 1 -C 6 alkyl, halosubstituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 3 when Z is a valence bond, R 3 must be hydrogen;
  • Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation nd breakdown of the blood aqueous barrier in a mamma., including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (93) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkenyl refers to straight or branched hydrocarbon chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and
  • alkoxy refers to -O-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
  • alkylthio refers to -S-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and t-butylthio.
  • cycloalkyl refers to cyclic hydrocarbon radicals including, but not limited to cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • one or more substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
  • excess lacrimation refers to a degree of lacrimation that is higher than the desired degree of lacrimation.
  • R 3 is a group of the formula II
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in United States Patent 5,162,339, which issued on November 11, 1992. This patent is incorporated herein by reference in its entirety.
  • R 3 is a group of the formula III
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in PCT Patent Application PCT/US 91/02853, which designates the United States, was filed in the United States Receiving Office on April 25, 1991 and was published as WO 91/18899 on December 12, 1991. This application is incorporated herein by reference in its entirety.
  • R 3 is a group of the formula IV, V or VI
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in PCT Patent Application PCT/US 91/03369, which designates the United States, was filed on in the United States Receiving Office May 14, 1991 and was published as WO 92/01688 on February 6, 1992. This application is incorporated herein by reference in its entirety.
  • R 3 is a group of the formula VII
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in United States Patent 5,232,929, which issued on August 3, 1993, United States Patent Application 800,667, filed November 27, 1991, PCT Patent Application PCT/US 91/02541, which designates the United States, was filed in the United States Receiving Office on April 12, 1991 and was published as WO 91/18878 on December 12, 1991, and PCT Patent Application PCT/US 92/00065, which designates the United States, was filed in the United States Receiving Office on January 14, 1992 and was published as WO 92/17449 on October 15, 1992.
  • R 3 is a group of the formula IX
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in United States Patent Application Serial No. 719,884, filed June 21, 1991 and PCT Patent Application PCT/US 92/04697, which designates the United States and which was filed in the United States Receiving Office on June 11, 1992 and published as WO 93/00330 on January 7, 1993.
  • the compounds of the formulae Ia, Ib, Ic, Id, Ie, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII and XIX are useful as substance P receptor antagonists, i.e., they possess the ability to antagonize the effects of tachykinins at the substance P receptor site in mammals.
  • NK-1 antagonists are able to function as therapeutic agents in the treatment and prevention of disorders of the eye such as glaucoma, ocular hypertension, miosis, excess lacrimation and breakdown of the blood aqueous barrier in mammals, including humans.
  • the therapeutic agents that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids.
  • acids that form suitable pharmaceutically acceptable salts for use in this invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
  • salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a therapeutic agent from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base therapeutic agents of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • Those therapeutic agents of this invention that are also acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • the chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the therapeutic agents are those that form non-toxic base salts with the acidic therapeutic agents.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • therapeutic agents and their pharmaceutically acceptable salts exhibit substance P receptor binding activity. They and other NK-1 antagonists are of value in the treatment and prevention of glaucoma, ocular hypertension, miosis, excess lacrimation and breakdown of the blood aqueous barrier in mammals, including humans.
  • substance P receptor antagonists that are expected to exhibit activity for the treatment and prevention of the foregoing eye disorders in mammals, including humans, are those compounds described in the following references: European Patent Application EP 499,313, published August 19, 1992; European Patent Application EP 520,555, published December 30, 1992; European Patent Application EP 522,808, published January 13, 1993, European Patent Application EP 528,495, published February 24, 1993, PCT Patent Application WO 93/14084, published July 22, 1993, PCT Patent Application WO 93/01169, published January 21, 1993, PCT Patent Application WO 93/01165, published January 21, 1993, PCT Patent Application WO 93/01159, published January 21, 1993, PCT Patent Application WO 92/20661, published November 26, 1992, European Patent Application EP 517,589, published December 12, 1992, European Patent Application EP 428,434, published May 22, 1991, and European Patent Application EP 360,390, published March 28, 1990.
  • the therapeutic agents and the pharmaceutically acceptable salts thereof, as well as other NK-1 antagonists can be administered via either the oral, topical or parenteral routes.
  • these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of about 0.001 mg to about 21 mg per kg of body weight per day is most desirably employed.
  • the preferred dosage for oral administration is from about 0.001 to about 5 mg per kg of body weight per day.
  • Ointments or eyedrops will preferably contain the active agent in a concentration of about 0.01 to about 5 percent, more preferably about 1%.
  • Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the therapeutic agents, and their pharmaceutically acceptable salts, as well as other NK-1 antagonists may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses.
  • the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a therapeutic agent in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the activity of the therapeutic agents as substance P receptor antagonists may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography.
  • the substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry. Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC 50 values for each compound tested.
  • bovine caudate tissue is removed from a -70°C freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloride buffer having a pH of 7.7.
  • Tris i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol
  • the homogenate is centrifuged at 30,000 ⁇ G for a period of 20 minutes.
  • the pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 ⁇ G for another twenty-minute period.
  • the pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 4 ⁇ g/ml of bacitracin, 4 ⁇ g/ml of leupeptin, 2 ⁇ g of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
  • the radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 ⁇ l of the test compound made up to a concentration of 1 ⁇ M, followed by the addition of

Abstract

The present invention relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, excess lacrimation, hyperemia and breakdown of the blood aqueous barrier in mammals, including humans, using an NK-1 antagonist. It also relates to a method of treating or preventing such disorders in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, pyrrolidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds that are substance P receptor antagonists.

Description

NK-1 RECEPTOR ANTAGONISTS
FOR THE TREATMENT OF EYE DISORDERS
The present invention relates to a method of treating or preventing a disorder of the eye selected from glaucoma ocular hypertension, miosis, excess lacrimation, hyperemia and breakdown of the blood aqueous barrier in mammals, including humans, using an NK-1 antagonist. It also relates to a method of treating or preventing such disorders in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, pyrrolidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds that are substance P receptor antagonists.
The following references refer, collectively, to quinuclidine, piperidine, ethylene diamine, pyrrolidine and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: United States Patent 5,162,339, which issued on November 11, 1992; United States Patent 5,232,929, which issued on August 3, 1993; World Patent Application WO 92/20676, published November 26, 1992; World Patent Application WO 93/00331, published January 7, 1993; World Patent Application WO 92/21677, published December 10, 1992; World Patent Application WO 93/00330, published January 7, 1993; World Patent Application WO 93/06099, published April 1, 1993; World Patent Application WO 93/10073, published May 27, 1993; World Patent Application WO 92/06079, published April 16, 1992; World Patent Application WO 92/12151, published July 23, 1992; World Patent Application WO 92/15585, published September 17, 1992; World Patent Application WO 93/10073, published May 27, 1993; World Patent Application WO 93/19064, published September 30, 1993; World Patent Application WO 94/08997, published April 28, 1994; World Patent Application WO 94/04496, published March 3, 1994; United States Patent Application 988,653, filed December 10, 1992; United States Patent Application 026,382, filed March 4, 1993; United States Patent Application 123,306, filed September 17, 1993, and United States Patent Application 072,629, filed June 4, 1993. All of the foregoing World Patent Applications designate the United States and were filed in the U.S. Receiving Office of the PCT. The foregoing patents and patent applications are incorporated herein by reference in their entirety.
Beding-Barnekow et al. Br. J. Pharmacol. 95 (1), 259-67 (Sept. 1988) have reported that substance P is a mediator of miosis and breakdown of the blood aqueous barrier in rabbit eyes. Mandahl, A., Eur. J. Pharmacol., 114 (2), 121-27 (1985) has reported that the substance P receptor antagonist (D-Argsup 1, D-prosup 2, D-Trpsup 7 sup, sup 9, Leusup 1 sup 1) SP inhibited miosis in rabbits caused by echothiophate iodide or pilocarpine hydrochloride.
Krupin et al, EXP. Eye Res., 34 (3) 319-24 (1982) have reported that the administration of substance P into the third ventricle of rabbits resulted in a dose dependent increase in interocular pressure.
Holmdahl et al., Science, 214 1029-1031 (1981) have reported the results of studies which they state suggest that substance P or a related peptide is a neurogenic mediator of the inflammatory response in the eye, e.g., miosis (constriction of the pupil), hyperemia and breakdown of the blood aqueous barrier. Their studies showed that the substance P antagonist [D-Pro2, D-Trp79]SP inhibited inflammatory responses in the rabbit eye.
Summary of the Invention
This invention relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to such mammal an amount of a substance P receptor antagonist that is effective in treating or preventing such disorder.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to such mammal an amount of a NK-1 receptor antagonist that is effective in treating or preventing such disorder.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, and ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000006_0001
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of ring system A;
AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of AA;
AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the -CH2PR3 sidechain is attached to a carbon atom of ring AAA;
P is NR2, O, S, SO or SO2;
Q is SO2, NH,
Figure imgf000007_0001
or
Figure imgf000007_0002
wherein the point of attachment of said to
Figure imgf000007_0003
ring AAA is the nitrogen atom and the point of attachment to
X5 is the sulfur atom;
W1 is hydrogen, halo or (C1-C6) alkyl, S-(C1-C3) alkyl, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
W2 is hydrogen, (C1-C6) alkyl, S-(C1-C3) alkyl, halo or (C1- C6) alkoxy optionally substituted with from one to three fluorine atoms;
W is hydrogen, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, -S(O)v-(C1-C6) alkyl wherein v is zero, one or two, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
X1 is hydrogen, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms or (C1-C10) alkyl optionally substituted with from one to three fluorine atoms;
X2 and X3 are independently selected from hydrogen, halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)- alkylamino, di-(C1-C6)alkylamino,
Figure imgf000008_0004
, (C1-C6)-
Figure imgf000008_0001
, hydroxy(C1-C4) alkyl, (C1-C4) alkoxy(C1- C4)alkyl,
Figure imgf000008_0002
and
Figure imgf000008_0003
;
X5 is a four to six membered heterocyclic ring containing from one to three heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms and halo;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R1 is selected from amino, (C1-C6) alkylamino, di-(C1-C6)alkylamino, -S(O)v-(C1-C10)-alkyl wherein v is zero, one or two, -S(O)v-aryl wherein v is zero, one or two, -O-aryl, -SO2NR4R5 wherein each of R4 and R5 is, independently, (C1- C6)alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
Figure imgf000009_0001
,
Figure imgf000009_0002
,
Figure imgf000009_0003
Figure imgf000009_0004
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10)alkyl)2 and
Figure imgf000009_0006
; and wherein the aryl moieties of said -S(O)v-aryl, -O-aryl and
Figure imgf000009_0005
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from o
(C1-C4) alkyl, (C1-C4) alkoxy and halo;
or R1 is a group having the formula
or
Figure imgf000009_0007
Figure imgf000009_0008
wherein a is 0, 1 or 2 and the asteris), represents a position meta to the R2R3NCH2 side chain;
the dotted lines in formula Ib represent that one of the X-Y and Y-Z bonds may optionally be a double bond;
X is selected from =CH-, -CH2-, -O-, -S-, -SO-, -SO2-,
-N(R4)-, -NH-, =N-, -CH[(C1-C6) alkyl]-, =C[(C1-C6)alkyl]-,
-CH(C6H5)- and =C(C6H5)-;
Y is selected from C=O, C=NR4, C=S, =CH-, -CH2-, =C[(C1- C6)alkyl]-, -CH[(C1-C6)alkyl]-, =C(C6H5)-, -CH(C6H5)-, =N-, -NH-, -N(R4)-, =C(halo)-, =C(OR4)-, =C(SR4)-, =C(NR4)-, -O-,
-S- and SO2, wherein the phenyl moieties of said =C(C6H5)- and
-CH(C6H5)- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said =[(C1-C6)alkyl]- and -CH[C1-C6)alkyl]- may optionally be substituted with from one to three fluorine atoms;
Z is selected from =CH-, -CH2-, =N-, -NH-, -S-,
-N(R4)-, =C(C6H5)-, -CH(C6H5)-, -C[(C1-C6) alkyl]- and -CH[(C1-C6)alkyl]-;
or X, Y and Z, together with the two carbon atoms shared between the benzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;
R4 is (C1-C6) alkyl or phenyl;
R2 is hydrogen or -CO2(C1-C10) alkyl;
R3 is selected from
Figure imgf000011_0001
Figure imgf000012_0001
wherein R6 and R10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1-C3) alkoxy-carbonyl;
R7 is selected from (C3-C4) branched alkyl, (C5-C6) branched alkenyl, (C5-C7) cycloalkyl, and the radicals named in the definition of R6;
R8 is hydrogen or (C1-C6) alkyl;
R9 and R19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R9 and R19 may optionally be substituted with from one to three substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
Y1 is (CH2)1 wherein 1 is an integer from one to three, or Y1 is a group of the formula
Figure imgf000013_0001
;
Z1 is oxygen, sulfur, amino, (C1-C3) alkylamino or (CH2)n wherein n is zero, one or two;
x is an integer from zero to four;
y is an integer from zero to four;
z is an integer from one to six, wherein the ring containing (CH2)z may contain from zero to three double bonds, and one of the carbons of (CH2)z may optionally be replaced by oxygen, sulfur or nitrogen;
o is two or three;
p is zero or one; r is one, two or three;
R11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
X4 is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R14, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R15;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R17;
R12 is a radical selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6) alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, are wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1- C6)alkyl, (C1-C6) alkoxy- (C1-C6) alkyl, (C1-C6) -alkylamino,
,
Figure imgf000015_0001
Figure imgf000015_0005
Figure imgf000015_0003
and
Figure imgf000015_0004
; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1-C6) alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), cyano, hydroxy-(C1- C6)alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6) alkylamino,
Figure imgf000015_0002
Figure imgf000016_0003
,
Figure imgf000016_0005
, and the radicals set forth in the definition of R12;
R16 is
Figure imgf000016_0004
, NHCH2R18, SO2R18, GR20 CO2H or one of the radicals set forth in any of the definitions of R12, R14 and R15;
R17 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R12, R14 and R15; and
R18 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6)alkyl;
G is selected from the group consisting of CH2, nitrogen, oxygen, sulfur and carbonyl;
R20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
and
Figure imgf000016_0001
Figure imgf000016_0002
wherein B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH2)n or (CH2)n+1 may be optionally substituted with (C1-C6) alkyl or (C2-C6) spiroalkyl, and either any two of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbons of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
with the proviso that (a) when m is 0, one of R16 and R17 is absent and the other is hydrogen, (b) when R3 is a group of the formula VIII, R14 and R15 cannot be attached to the same carbon atom, (c) when R14 and R15 are attached to the same carbon atom, then either each of R14 and Rιs is independently selected from hydrogen, fluoro, (C1-C6) alkyl, hydroxy-(C1-C6) alkyl and (C1-C6) alkoxy- (C1-C6) alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3-C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R12 and R13 cannot both be hydrogen; (e) when R14 or R15 is attached to a carbon atom of X4 or (CH2)y that is adjacent to the ring nitrogen, then R14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom; and (f) neither R14, R15, R16 nor R17 can form a ring with R13;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
The fused bicyclic nucleus of compounds of the formula Ib to which W and the -CN2NR2R3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (1) through (47A) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(1) A compound of the formula Ia or Ib wherein the substituents at positions "2" and "3" of the nitrogen containing ring of R3 are in a cis configuration. (When R3 is a group of the formula VII or VIII, "a cis configuration", as used herein, means that the non-hydrogen substituent at position "3" is cis to R12).
(2) A compound of the formula la wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; A is phenyl or indolinyl; W is (C1-C3) alkoxy optionally substituted with from one to five fluorine atoms; and R is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, and R may optionally be substituted with one or two (C1-C3) alkyl moieties.
(3) A compound of the formula Ib wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; the fused bicyclic ring system to which W and the -CH2NR2R3 sidechain are attached is benzoxazolyl, benzisoxazolyl, benzthiazolyl or benzimidazolyl; and W is (C1-C6) alkoxy optionally substituted with from one to five fluorine atoms.
(4) A compound as defined in paragraph 1, 2 or 3 above wherein: (a) R3 is a group of the formula III and R9 is benzhydryl; (b) R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero and X4 is -(CH2)3-; or (c) R3 is a group of the formula IX, r is two and R19 is benzhydryl.
(5) A compound of the formula la wherein: (a) R3 is a group of the formula III wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, R9 is benzhydryl and A is pheryl; or (b) R3 is a group of the formula VII wherein R12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, A is phenyl, R12 is phenyl. each of R2, R13, R14, R15 and R16 is hydrogen, m is zero, W methoxy or isopropoxy, X4 is -(CH2)3- and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl or thiadiazolyl.
(6) A compound of the formula Ib wherein R3 is a group of the formula IX wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, R19 is benzhydryl, r is two and the fused bicyclic ring system to which W and the -CH2NR2R3 sidechain are attached is benzisoxazolyl or benzthiazolyl.
(7) A compound of the formula Ib wherein R3 is a group of the formula IX, R19 is benzhydryl, the fused bicyclic ring system to which W and the -CH2NR2R3 sidechain are attached is benzisoxazolyl, and W is methoxy.
(8) A compound of the formula Ib wherein R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero, X4 is -(CH2)3-, and the fused bicyclic ring system to which W and the -CH2NR2R3 sidechain are attached is benzothiazolyl, benzoxazolyl or benzimidazolyl.
(9) A compound of the formula la wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, m is zero, X4 is -(CH2)3-, A is phenyl, W is methoxy, and R is selected from thiazolyl, imidazolyl, thiadiazolyl and isoxazolyl.
(10) A compound of the formula Ia or Ib that is selected from:
(2S,3S)-3-[2-methoxy-5-(2-thiazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[5-(2-imidazolyl)-2-methoxybenzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(2-oxopyrrolidinyl)benzyl]amino¬2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(4-methyl-2-thiazolyl)benzyl]-amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(1,2,3-thiadiazol-4-yl)benzyl]-amino-2-phenylpiperidine;
(2S,3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine; (2S,3S)-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methoxybenzyl]- (2-phenylpiperidin-3-yl)amine;
(2S,3S)-3-[2-methoxy-5-(5-oxazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-(6-methoxy-2-methyl-benzoxazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine; and
(1SR,2SR,3SR,4RS)-3-[6-methoxy-3-methylbenzisoxazol-5-yl]methylamino-2-benzhydrylazanorbornane.
(11) A compound of the formula Ic, wherein R3 is a group of the formula II, III, VII or IX; R2 is hydrogen; ring AA is phenyl or indolinyl; W1 is (C1-C3)alkoxy optionally substituted with from one to three fluorine atoms; and R1 is
S(O)v-(C1-C10) alkyl wherein v is zero, one or two, S(O)v-aryl wherein v is zero, one or two, -O-aryl,
Figure imgf000020_0001
(C1-C10) alkyl wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10)alkyl)2 or
Figure imgf000020_0002
wherein said aryl is phenyl or benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy and halo.
(12) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula II, o is two, and each
R6 and R7 is phenyl.
(13) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, R12 is phenyl, m is zero and X4 is
-(CH2)3-.
(14) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula IX, R19 is benzhydryl and r is two.
(15) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula III, R8 is other than hydrogen and R9 is benzyhydryl. (16) A compound to the formula Ic wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration.
(17) A compound of the formula Ic wherein R3 is a group of the formula II wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, o is two, each of R6 and R7 is phenyl and ring AA is phenyl or indolinyl.
(18) A compound of the formula Ic wherein R3 is a group of the formula III wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, R8 is other than hydrogen, R9 is benzhydryl and ring AA is phenyl.
(19) A compound of the formula Ic wherein R3 is a group of the formula VII wherein R12 and the substituent at position M3" of the nitrogen containing ring are in the cis configuration, ring AA is phenyl, R12 is phenyl, each of R2,
R13, R14, R15 and R16 is hydrogen, m is zero, X4 is -(CH2)2- or
-(CH2)3- and R1 is selected from S(O)v-(C1-C10) alkyl wherein v is zero, one or two, and , and
Figure imgf000021_0001
di-(C1-C6)alkylamino.
(20) A compound as defined in paragraph 19 above, wherein X4 is -(CH2)2- and W1 is (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms.
(21) A compound as defined in paragraph 19 above, wherein X4 is -(CH2)3- and W1 is (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms.
(22) A compound of the formula Ic, wherein R3 is a group of the formula IX wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, r is two and R19 is benzhydryl.
(23) A compound as defined in paragraph 22 above, wherein ring AA is phenyl, W1 is (C1-C3) alkoxy optionally substituted with from one to three fluorine atoms and R1 is selected from -S(O)v-(C1-C10) alkyl wherein v is zero, one or two, di-(C1-C6) alkylamino and
Figure imgf000022_0003
(24) A compound as defined in paragraph 15 above, wherein ring AA is phenyl, W1 is (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from -S(O)v-(C1-C10) alkyl wherein v is zero, one or two, and
Figure imgf000022_0002
(25) A compound as defined in paragraph 15 above, wherein ring AA is phenyl, W1 is (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from amino, (C1-C6) alkylamino or di-(C1-C6)alkylamino.
(26) A compound as defined in paragraph 12 above, wherein ring AA is phenyl, W1 is (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from -S(O)v-(C1-C10) alkyl wherein v is zero, one or two, and
Figure imgf000022_0001
(27) A compound as defined in paragraph 12 above, wherein ring AA is phenyl, W1 is (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from amino, (C1-C6) alkylamino or di-(C1-C6)alkylamino.
(28) A compound as defined in paragraph 24 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(29) A compound as defined in paragraph 25 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(30) A compound as defined in paragraph 26 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2R3 containing side chain. (31) A compound as defined in paragraph 27 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(32) A compound as defined in paragraph 13 above, wherein ring AA is phenyl, W1 is selected from isopropoxy, OCF3, OCH3, OCHF2 and OCH2CF3, and R1 is selected from -S(O)v- (C1-C10) alkyl wherein v is zero, one or two, and (C1-C10)alkyl-N-SO2-(C1-C10) alkyl.
(33) A compound selected from the group consisting of:
(2S,3S)-N-(2-methoxy-5-methylsulfonylphenyl)-methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(2-methoxy-5-methylthiophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(2-methoxy-5-dimethylaminophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S, 3S) -N-(5-trifluoroacetylaroino-2-methoxyphenyl)methyl-2-diphenylmethyl-i-azabicyclo-[2.2.2]octan-3-amine.
(34) A compound of the formula Ic, wherein R' is a group of the formula VII, m is zero, each of R1 , R2, R3 and R17 is hydrogen, R12 is phenyl, R14 is
Figure imgf000023_0001
, ring AA is phenyl, W1 is (C1-C3) alkoxy and R1 is selected from (C1-C5)alkyl, -SCH3, SO2CH3, SOCH3, (C1-C6) alkylamino and di-(C1-C6)alkyl-amino.
(35) A compound of the formula Ic, having the formula
Figure imgf000024_0001
(36) A compound of the formula Id wherein R6, R10, R11 and R13 are phenyl, R8 is hydrogen, R9 is phenyl optionally substituted with chlorine, fluorine, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, m is O and n is 3 or 4.
(37) A compound of the formula Id that is selected from the group consisting of:
(2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S,3S)-3(-5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxy-phenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)-benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine; (2S,3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)-aminopiperidine; and
(2S,3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidine.
(38) A compound of the formula Id, wherein R3 is a group of the formula II wherein o is two or three and each of R6 and R7 is phenyl or substituted phenyl.
(39) A compound of the formula Id, wherein R3 is a group of the formula III, R8 is hydrogen and R9 is phenyl or substituted phenyl.
(40) A compound of the formula Id, wherein R3 is a group of the formula IV wherein 1 is one or two and each of R10 and R11 is phenyl or substituted phenyl.
(41) A compound of the formula Id, wherein R3 is a group of the formula V wherein n is zero or one and each of R10 and R11 is phenyl or substituted phenyl.
(42) A compound of the formula Id, wherein R3 is a group of the formula VI wherein p is one and each of R10 and Ru are phenyl or substituted phenyl.
(43) A compound of the formula Id, wherein R3 is a group of the formula VII wherein q is two, three or four, m is zero and R12 is phenyl or substituted phenyl.
(44) A compound of the formula Id, wherein R3 is a group of the formula VIII wherein y is zero, x is zero or one, z is three or four, m is zero and R12 is phenyl or substituted phenyl.
(45) A compound of the formula Id wherein R3 is a group of the formula VII, R6, R14, R13 R16 and R15 are hydrogen, R12 is phenyl, X1 is 2-methoxy, X2 and X3 are independently selected from hydrogen, chlorine, fluorine, methyl, (C1-C6) alkoxy and trifluoromethane, m is 0 and q is 3 or 4.
(46) A compound of the formula Id wherein R3 is a group of the formula VII and said compound is selected from the group consisting of: cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;
cis-3-(2-trifluoromethylbenzylamino)-2-phenyl-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-methylphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methylphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-thienyl)-piperidine; cis-3-(2-methoxybenzylamino)-2-phenylazacyclo-heptane;
3-(2-methoxybenzylamino)-4-methyl-2-phenyl-piperidine;
3-(2-methoxybenzylamino)-5-methyl-2-phenyl-piperidine; 3-(2-methoxybenzylamino)-6-methyl-2-phenyl-piperidine;
(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-carboethoxypent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(6-hydroxy-hex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5,6-dihydroxyhex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine; cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxy-5-methylbenzylamino)-2-phenyl-piperidine;
(2S,3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenylpiperidine;
(2S,3S)-3-(2-methoxybenzylamino)-1-(5-N-methylcarboxamidopent-1-yl)-2-phenylpiperidine;
(2S,3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-aminopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(2,5-dimethoxybenzy1amino)-2-phenylpiperidine;
cis-3-(3,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(4,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2,5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-2-phenylpiperidine;
cis-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1-yl)-2-phenylpiperidine;
cis-1- (5,6-dihydroxyhex-1-yl)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine; cis-2-phenyl-3-[-2(prop-2-yloxy)benzylamino]piperidine; cis-3-(2,5-dimethoxybenzyl)amino-2-(3-methoxyphenyl)piperidine hydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-methoxyphenyl)piperidine dihydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-chlorophenyl)piperidine dihydrochloride;
3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;
(2S,3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenylpiperidine; and
(2S,3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenylpiperidine.
(47) A compound of the formula Id, wherein R3 is a group of the formula II or III and said compound is selected from the group consisting of:
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; (2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S,3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine.
(47A) a compound of the formula Ie that is selected from the group consisting of:
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;
N-(4,5-dimethylthiazol-2-yl)-N-[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-yl-aminomethyl)phenyl]-methanesulfonamide;
{5-[(4,5-dimethylthiazol-2-yl)methylamino]-2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-yl)amine;
{5-(4,5-dimethylthiazol-2-ylamino)-2-methoxybenzyl}- ((2S,3S)-2-phenylpiperidin-3-ylamine;
4,5-dimethylthiazole-2-sulfonic acid methyl-[3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)-4-trifluoromethoxyphenyl]-amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide; and
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human comprising administering to said mammal an amount of a compound having the formula
Figure imgf000030_0001
wherein W is Y or X(CH2)n;
Y is optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl or optionally substituted (C3-C8)cycloalkyl;
X is optionally substituted (C1-C6) alkoxy, hydroxy, CONR1R2, CO2R1, CHR1OR2, CHR1NR2R3, COR1, CONR1OR2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
Ar1, Ar2 and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl. phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and R1, R2 and R3 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C8) cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C1-C5) heterocyclic groi; s, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;
and wherein the substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl and trifluoromethoxy;
and wherein the substituents on the foregoing substituted (C1-C5) heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C1-C4) alkyl when attached to a ring sulfur atom, and are independently selected from oxygen and (C1-C4) alkyl when attached to a ring nitrogen atom;
and wherein the substituents on said substituted Ar1 groups are independently selected from (C1-C6) alkyl optionally substituted with from one to three halo groups, (C1-C6) alkoxy optionally substituted with from one to three halo groups, (C1-C6)alkylsulfinyl, (C2-C6) alkenyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, and di-(C1-C6) alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C1-C6)alkylsulfonyl, or (C1-C6)alkylsulfinyl group;
and wherein the substituents on said substituted Ar2 and Ar3 groups are independently selected from (C1-C4) alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, di-(C1-C4)alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C1-C4) alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (48) through (54) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder. (48) A compound of the formula X, wherein W is X(CH2)n.
(49) A compound of the formula X, wherein W is Y.
(50) A compound of the formula X, wherein Ar1 is substituted aryl and W is Y.
(51) A compound of the formula X, wherein Ar1 is mono-, di- or tri-substituted phenyl and W is Y.
(52) A compound of the formula X, wherein Ar1 is phenyl disubstituted at the 2- and 5-positions and W is Y.
(53) A compound of the formula X, wherein Ar1 is paramethoxyphenyl, each of Ar2 and Ar3 is phenyl and W is Y.
(54) A compound of the formula X that is selected from the group consisting of:
(3R,4S,5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo-[2.2.2]octane-3-carboxylie acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamin)o-6-diphenylmethyl-1-azabicyclo[2.2.2]octane -carboxylic acid;
(3R,4S,5S,6S)-5-(5-N-methyl-methar sulfonylamino-2-methoxy-benzylamino) -6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid; (3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)- 6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-N-methylmethanesulfonylamino-2-methoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid; (3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid; and
(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma and ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula
Figure imgf000034_0001
wherein R1 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, amino, trihaloalkoxy (e.g., trifluoromethoxy),
Figure imgf000035_0001
1 6 , alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, amino, phenyl, trihaloalkoxy (e.g., trifluoromethoxy) -
Figure imgf000036_0001
,
one of R5 and R6 is hydrogen and the other is selected from hydroxymethyl, hydrogen, (C1-C3) alky
Figure imgf000036_0004
l, (C1-C8)acyloxy- (C1-C3) alkyl, (C1-C8)alkoxymethyl and benzyloxymethyl;
R7 and R8 are independently selected from hydrogen, (C1- C3) alkyl and phenyl;
R9 is selected from methyl, hydroxymethyl,
Figure imgf000036_0003
R14R15NCO2CH2-, R16OCO2CH2-, (C1-C4) alkyl-CO2CH2-, -CONR17R18, R17R18NCO2-, R19OCO2-, C6H5CH2CO2CH2-, C6H5CO2CH2-, (C1-C4) alkyl- CH(OH)-, C6H5CH(OH)-, C6H5CH2CH(OH)-, CH2halo, R20SO2OCH2, -CO2R16 and R21CO2-;
R10 and R11 are independently selected from hydrogen, (C1- C3) alkyl and phenyl;
R12 is hydrogen, benzyl or a group of the formula
Figure imgf000036_0002
wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R23;
R13, R14, R15, R16, R17, R18, R19, R20, R21 and R24 are independently selected from hydrogen, (C1-C3)alkyl and phenyl; R22 and R23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy (C1-C6) alkyl, (C1- C6)alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy, (C1-C6)-
Figure imgf000037_0002
Figure imgf000037_0003
(C1-C6) straight or branched alkyl, (C3- C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2- C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1- C6) alkoxy optionally substituted with from one to three fluorine atoms,
Figure imgf000037_0001
y , ;
wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached form a second pyrrolidine ring; with the proviso that when R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R12 is absent or R12 is present and the nitrogen of the second pyrrolidine ring is positively charged; or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Compounds of the formula XI that contain two pyrrolidine rings may be represented by one of the following two structures, depending on whether R12 is present or absent.
Figure imgf000038_0001
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier and ocular hypertension in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (55) through (59) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(55) A compound of the formula XI wherein R1 is benzhydryl.
(56) A compound of the formula XI wherein R1 is diphenylmethyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10, and R11 is hydrogen, R9 is selected from hydroxymethyl, methoxymethyl, -CO2R16, -CONR17R18, R14R15NCO2CH2-, R16OCO2CH2-, (C1-C4)alkyl-CO2CH2-, C6H5CH2CO2CH2-, -CH2halo and R20SO2OCH2-, and R12 is hydrogen or benzyl.
(57) A compound of the formula XI wherein R1 is phenyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substiuents, each of R5, R6, R7, R8, R10, and R11 is hydrogen, R9 is selected from hydroxymethyl, methoxymethyl, -CO2R18, -CONR17R18, R14R15NCO2CH2CH2-, R16OCO2CH2-, (C1-C4) alkyl-CO2CH2-, -CH2halo, R20SO2OCH-, and R12 is hydrogen or benzyl.
(58) A compound of the formula XI wherein R1 is diphenylmethyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10, R11 and R13 is hydrogen, and wherein R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen).
(59) A compound of the formula XI that is selected from the group consisting of:
(2S, 3S, 4R)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethyIphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine; (2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5- (methylethyl)phenyl)methylamino]-4-(carbomethoxymethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5- (methylethyl)phenyl)methylamino]-4-(carboxymethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5- (methylethyl)phenyl)methylamino]-4-(2-dimethylamino-carbamoylethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2S, 3S, 4R)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-methoxyethyl)-pyrrolidine;
(2S, 3S, 4R)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-methoxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methyl-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethyIphenyl)-methylamino]-bicyclo[2.2.1]-heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane; (1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]bicyclo- [2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo- [2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]bieyelo- [2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-propyIphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylpropyl)phenyl)methylamino]bicyclo- [2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-phenyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR, 2SR, 3RS, 4RS)-1-aza-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(2SR, 3SR, 4RS)-N-1-phenylmethyl-2-diphenylmethyl-3- [(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethy1-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-propyIphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine; (2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methyl-1-propyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-trifluoromethoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-chlorophenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-phenyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-phenyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine; and
(2SR, 3SR, 4RS)-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000042_0001
wherein R1 is hydrogen, (C1-C8) alkyl, a saturated (C6-C10) carbocyclic ring system containing two fused rings, a saturated (C6-C10) carbocyclic bridged ring system containing o rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C8) alkoxy optionally substituted with from one to three fluorine atoms;
R2 is hydrogen, benzyl or a group of the formula
Figure imgf000043_0003
wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R9;
R8 and R9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C1-C6) alkyl,
(C1-C6) alkylamino, di-(C1-C6)alkylamino, (C1-C6) alkoxy,
Figure imgf000043_0001
Figure imgf000043_0002
y , (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, amino, (C1-C6) -alkylamino,
Figure imgf000044_0003
Figure imgf000044_0001
and
Figure imgf000044_0002
- ; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
R4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl gr os may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, phenyl, amino, (C1-C6) alkylamino,
Figure imgf000045_0002
,
Figure imgf000045_0003
, ,
Figure imgf000045_0001
R3 is hydrogen, (C3-C8) cycloalkyl, (C1-C6) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
Rs is hydrogen, (C1-C6) alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R6 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, trifluoromethyl, amino, trihaloalkoxy
Figure imgf000046_0001
R12 is hydrogen, (C1-C3) alkyl or phenyl;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (60) through (62) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(60) A compound of the formula XII wherein R2 is hydrogen, or R2 and R1, together with the nitrogen to which they are attached, form a monocyclic ring containing five to seven carbon atoms; R3 is hydrogen, methyl or phenyl; R5 is hydrogen; R4 is phenyl or indanyl, wherein said phenyl or indanyl may optionally be substituted with from one to three substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C1-C6) alkylamino, -C(O)NH-(C1-C8) alkyl, (C1-C6)alkyl-C(O)-, -C(O)-O-(C1-C6) alkyl, -C(O)H, -CH2OR12, -NH(C1-C6) alkyl, -NHC(O)H, -NHC(O)-(C1-C6)alkyl, -NHSO2(C1-C6)alkyl and (C1-C6)alkyl-N-SO2-(C1-C6) alkyl; and R6 is phenyl.
(61) A compound of the formula XII wherein R1 is alkyl, R6 is unsubstituted phenyl, R4 is a monosubstituted or disubstituted aryl group that is substituted at the C-2 position with an alkoxy group or substituted at the C-5 position with an alkyl, alkoxy or trihaloalkoxy group, or substituted in such manner at both C-2 and C-5 positions (i.e., with an alkoxy group at the C-2 position and an alkyl, alkoxy or trihaloalkoxy group at the C-5 position), and each of R2, R3 and R5 is hydrogen.
(62) A compound of the formula XII that is selected from the group consisting of:
1-N-cyclohexyl-1-phenyl-2-N,-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-trifluoromethoxyphenyl)methyl]-1,2-ethanediamine;
1-N-pyrrolidyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-methyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclopentyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-propyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-phenylmethyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclooctyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclobutyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine; 1-N-(2-adamantyl)-1-phenyl-2-N'-[(2-mathoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(1,1-dimethylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-isopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(1-phenylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(2-norbornyl)-1-phenyl-2-N'-[ (2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-tert-butyIphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-isopropyIphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-4,5-dimethyIphenyl)methyl]-1,2-ethanediamine; and
1-N-cyclohexyl-1-N-(6-hydroxyhexyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000048_0001
wherein R1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
R2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
R3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl, or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (63) through (65) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(63) A compound of the formula XIII, wherein R1 is phenyl or substituted phenyl.
(64) A compound of the formula XIII, wherein R1 is methoxyphenyl.
(65) A compound of the formula XIII, wherein said compound is (+)-cis-9-diphenylmethyl-N-((2-methoxy¬phenyl)methyl)-10-azatricyclo[4.4.1.05,7]undecan-8-amine.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal. including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000050_0001
XIV
wherein m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8;
w is an integer from 0 to 2;
y is an integer from 1 to 4;
z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH2)z may optionally be substituted with R4;
R1 is hydrogen or (C1-C8) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
R2 is a group selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, amino,
Figure imgf000051_0001
R5 is hydrogen, phenyl or (C1-C6) alkyl;
or R2 and R5, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
R3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, phenyl, amino, (C1-C6) alkylamino, (C1-C6)dιalkyl amino,
Figure imgf000052_0001
and
Figure imgf000052_0002
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), nitrile,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
h
Figure imgf000052_0003
set forth in the definition of R2;
R6 is
Figure imgf000052_0004
, NHCH2R9, NHSO2R9 or one of the groups set forth in any of the definitions of R2, and R4;
R8 is oximino (=NOH) or one of the groups set forth in any of the definitions of R2, and R4;
R9 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
with the proviso that (a) when m is O, R8 is absent and R6 is hydrogen, (b) neither R4, R6, nor R8 can form, together with the carbon to which it is attached, a ring with R5, (c) the sum of y and z must be less than 7; or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (66) through (68) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(66) A compound of the formula XIV, wherein R2 is a radical selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, amino,
Figure imgf000053_0001
Figure imgf000053_0002
,
Figure imgf000053_0003
and
Figure imgf000053_0004
alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl.
(67) A compound of the formula XIV, wherein R2 is a group selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, amino,
(C1-C6) -alkylamino,
Figure imgf000053_0006
,
Figure imgf000053_0005
Figure imgf000054_0001
Figure imgf000054_0004
,
Figure imgf000054_0003
and
Figure imgf000054_0002
; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), nitrile,
(C1-C6) alkylamino, di- (C1-C6) alkylamino, (C1-C6) alkoxy,
Figure imgf000054_0005
and phenyl.
(68) A compound of the formula XIV, wherein said compound is (3RS,4RS)-3-phenyl-4-(2-methoxybenzyl)amino-2-azabicyclo[3.3.1]nonane.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma and ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
wherein X1 is C1-C5 alkoxy or halosubstituted (C1-C3) alkoxy;
X2 is hydrogen, halogen, (C1-C5) alkyl, (C2-C3) alkenyl, (C2-C5)alkynyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, halosubstituted (C1-C5) alkyl, halosubstituted (C1-C5) alkoxy, (C1-C5) alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C1-C5) alkylsulfonylamino (which may be substituted by halogen),
Figure imgf000055_0001
(which may be substituted by halogen in the alkylsulfonyl moiety), (C1-C5) alkanoylamino (which may be substituted by halogen) or
Figure imgf000055_0002
(which may be substituted by halogen in the alkanoyl moiety);
Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
A is Y-(CH2)m-CH(R2)-(CH2)n-NR1-;
R1 is hydrogen, (C1-C5) alkyl, benzyl or -(CH2)p-Y;
R2 is hydrogen, (C1-C5) alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)p-Y;
Y is -CN, -CH2Z or -COZ; Z is hydroxy, amino, (C1-C5) alkoxy, (C1-C5) alkylamino or dialkylamino having frcώ 1 to 5 carbon atoms in each alkyl moiety;
m, n and p are each, independently, 0, 1, 2 or 3; and R1 and R2 may be connected to form a ring;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(69) A compound of the formula XV, wherein said compound is selected from the group consisting of:
(3R,4S,5S,6S)-N-carbamoylmethy1-5-(5-isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-N-carboxymethyl-5-(5-isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-3-(2-carbamoylpyrrolidin-1-yl)carbonyl-5- (5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane;
(3R*,4S*,5S*,6S*)-N-(1-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-N-(1-carbamoyl-3-methylbutyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide; and
(3R,4S,5S,6S)-N-(2-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide. This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000057_0005
wherein R1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)-alkylamino, di-(C1-C6) alkylamino,
Figure imgf000057_0001
,
Figure imgf000057_0002
, hydroxy(C1-C4) alkyl,
Figure imgf000057_0003
,
Figure imgf000057_0004
, (C1-C4) alkoxy (C1-C4) alkyl, -S(O)v- (C1-C10)-alkyl wherein v is zero, one or two, -S(O)v-aryl wherein v is zero, one or two, -O-aryl, -SO2NR4R5 wherein each of R4 and R5 is, independently, (C1-C6) alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, wherein one or both
Figure imgf000058_0002
of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10)alkyl)2 and ; and wherein the aryl moieties of
Figure imgf000058_0001
said -S(O)v-aryl, -O-aryl and
Figure imgf000058_0003
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy and halo;
or R1 is phenyl substituted with a group having the formula
or
Figure imgf000058_0004
Figure imgf000058_0005
wherein a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R;
R2 is selected from (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituents, independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6)-alkylamino, ,
,
Figure imgf000059_0004
Figure imgf000059_0002
,
Figure imgf000059_0003
; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
m is an integer from 0 to 8 , and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R4;
R3 is selected from
Figure imgf000059_0001
NHCH2R8, SO2R8, AR9, CO2H and the radicals set forth in the definitions of R2, R6 and R7;
A is CH2, nitrogen, oxygen, sulfur or carbonyl;
R8 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
R4 is selected from oximino (=NOH) and the radicals set forth in the definitions of R2, R6 and R7;
R9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
and
Figure imgf000060_0004
Figure imgf000060_0005
wherein B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH2)n and (CH2)n+1 may be optionally substituted with (C1-C6) alkyl or (C2-C6) spiroalkyl; and either any one pair of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
X is (CH2)q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R6, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R7;
R6 and R7 are independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), cyano, hydroxy-(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
Figure imgf000060_0001
Figure imgf000060_0002
,
Figure imgf000060_0003
,
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
( ,
Figure imgf000061_0004
and the radicals set forth in the definition of R2; and
Y is (CH2)z wherein z is zero or one;
with the proviso that: (a) when A is -(CH2)- or carbonyl, R9 cannot be furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl or thienyl; (b) when m is zero, one of R3 and R4 is absent and the other is hydrogen; and (c) when R6 or R7 is attached to a carbon atom of X that is adjacent to the ring nitrogen, then R6 or R7, respectively, must be a substituent wherein the point of attachment is a carbon atom;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (70)-(75) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(70) A compound of the formula XVI wherein z is one.
(71) A compound of the formula XVI wherein q is three.
(72) A compound of the formula XVI wherein q is three, m is zero, R3 is hydrogen and R4 is absent.
(73) A compound of the formula XVI wherein R1 is phenyl substituted with from one to three substituents independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three flourine atoms. (74) A compound of the formula XVI wherein z is one, m is zero, R4 is absent, and each of R3, R6 and R7 is hydrogen.
(75) A compound of the formula XVI that is selected from the group consisting of:
(±)-[3R-[3α, 6α (R*)]]-3-phenyl-7-phenyl-1,8-diazaspiro[5.5]undecane; and
(±)-[3R-[3α, 6α (R*)]]-3-(2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane.
Other compounds of the formula I include the following: (±)-[3R-[3α, 6α (R*)]]-3-(2-methoxy-5-trifluoromethoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*)]]-3-(5-chloro-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*)]]-3-(5-isopropyl-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*)]]-3-(5-tert.butyl-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*)]]-3-(2-nethoxy-5-(N-methyl-N-methylsulf onylaminophenyl ) -7 -phenyl-1 , 8 -diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*)]]-3-(2-iodophenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*)]]-3-(2-methoxy-4-methylphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(+)-[3R-[3α, 6α (R*)]]-3-(2-isopropoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α, 6α (R*) ]]-3-(2-difluoromethoxy-5-t r i f luoromethoxypheny l ) - 7 -ph eny l - 1 , 8 -diazaspiro[5.5]undecane;
(±)-[3R-[3α 5α (R*)]]-3-(2-methoxyphenyl)-6-phenyl- 1,7-diazaspiro[4.5]decane;
(±.)-[3R-[3α, 5α (R*)]]-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane;
(±)-[3R-[3α, 5α (R*)]]-3-(5-chloro-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane; (±)-[3R-[3α,5α(R*)]]-3-(5-isopropyl-2-methoxyphenyl)- 6-phenyl-1,7-diazaspiro[4.5]decane; and
(±)-[3R-[3α, 5α (R*)]]-3-(5-tert.butyl-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000063_0001
wherein Ar1 and Ar2 are each independently aryl or substituted aryl;
R1 is alkyl having from 1 to 6 carbon atoms;
R2 is hydrogen or alkyl having from 1 to 6 carbon atoms; and either X and Y are taken separately and they are each, independently, hydrogen, dialkylphosphoryl having from 2 to 12 carbon atoms, alkyl having from 1 to 6 carbon atoms; or X and Y are taken together and they represent a hydrocarbon chain having 3, 4, or 5 carbon atoms, optionally containing up to 2 double bonds and optionally having 1 or 2 substituents selected from oxo, hydroxy and alkyl having from 1 to 6 carbon atoms;
provided that when X and Y are taken together they are attached to adjacent carbon atoms; and provided that if either X or Y is hydrogen, then the other one must be alkenyl or alkynyl;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
The term "alkylthio" is used in formula XVII to mean -SR4 (R4 is alkyl) including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio and the like.
The term "dialkylphosphoryl" is used in formula XVII to mean -P(O) (OR5) (OR6) (R5 and R6 are alkyl) including, but not limited to, diethylphosphoryl, ethylmethylphosphoryl and the like.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (76) - (79) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(76) Compounds of formula XVII wherein Ar1 and Ar2 are each phenyl, R1 is methyl, R2 is hydrogen, X is alkenyl or alkynyl and Y is hydrogen.
(77) Compounds of the formula XVII wherein Ar1 and Ar2 are each phenyl, R1 is methyl, R2 is hydrogen and X and Y are each alkyl.
(78) Compounds of the formula XVII wherein Ar1 and Ar2 are each phenyl, R1 is methyl, R2 is hydrogen and X and Y represent CH2CH2CH2 or CH2CH2CH2CH2.
(79) A compound of the formula XVII that is selected from:
(2S,3S)-N-(5-Isopropenyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(2-Methoxy-5-vinyIphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; (2S,3S)-N-(2-Methoxy-4,5-dimethylphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5,6,7,8-Tetrahydro-3-methoxy-2-naphthyl)methyl-2-diphenylmethy1-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-Methoxyindan-6-yl)methy1-6-diphenylmethyl- 1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-3-(2,4-Dimethoxy-5-ethylbenzylamino)-2-diphenylmethyl-1-azabicyclo[2.2.2.]octane; and
(2S,3S)-2-Diphenylmethyl-N-[2-methoxy-5- (diethylphosphoryl)phenyl]methyl-1-azabicyclo[2.2.2]octan-3-amine.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
Figure imgf000065_0001
wherein Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
X is -CONR3R4, -CO2R3, -CH2OR3, -CH2NR3R4 or -CONR3OR4;
R1, R.3 and R4 are each, independently, hydrogen or alkyl having 1 to 4 carbon atoms;
R2 is alkyl having 1 to 4 carbon atoms; Y is alkylsulfonyl having 1 to 4 carbon atoms, N-alkylN-alkanoylamino (which may be substituted by halogen in the alkanoyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkanoyl moieties, N-alkyl-N-alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkyl sulfonyl moieties, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, halosubstituted alkyl having 1 to 4 carbon atoms, alkylamino having 1 to 4 carbon atoms, alkanoylamino (which may be substituted by halogen) having 1 to 4 carbon atoms or alkylsulfonylamino (which may be substituted by halogen) having 1 to 4 carbon atoms;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (80) - (86) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(80) A compound of the formula XVIII wherein Ar1 and Ar2 are each phenyl.
(81) A compound as described in paragraph (80) wherein R2 is methyl and R1 is hydrogen.
(82) A compound as described in paragraph (81) wherein X is at the 3-position of the quinuclidine ring and X is carboxy or aminocarbonyl.
(83) A compound as described in paragraph (82) wherein
Y is said alkenyl.
(84) A compound as described in paragraph (83) wherein
Y is isopropenyl. (85) A compound as described in paragraph (82) wherein Y is methylsulfonyl, N-acetyl-N-methylamino or N-methyl-N-methylsulfonylamino.
(86) A compound of the formula XVIII that is selected from:
(3R,4S,5S,6S)-5-(5-Isopropenyl-2-methoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-6-Diphenylmethyl-5-(2-methoxy-5-methylsulfonylbenzylamino)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-5-[5-(N-Acetyl-N-methylamino)-2-methoxybenzylamino]-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-6-Diphenylmethyl-5-[2-methoxy-5-(N-methyl-N-methylsulfonylamino)benzy1amino]-1-azabicyclo[2.2.2]octane-3-carboxamide; and
(3R,4S,5S,6S)-6-Diphenylmethyl-5-(2-methoxy-5-methylsulfonylbenzylamino)-1-azabicyclo[2.2.2]octane-3-carboxylic acid.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
Figure imgf000068_0001
wherein R is C1-C6 alkyl;
X is C1-C6 alkyl having one or more substituents bonded through a heteroatom;
Ar1 and Ar2 are each, independently, aryl optionally substituted by one C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, phenoxy, mono C1-C6 alkylamino, di C1-C6 alkylamino, halosubstituted C1-C6 alkyl, or halosubstituted C1-C6 alkoxy;
Y is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Z-(CH2)p-, or W-(CH2)m-CHR2-(CH2)n-NR1CO- wherein Y is at the 4-, 5- or 6-position on the quinuclidine ring;
R1 is hydrogen, C1-C6 alkyl, benzyl or -(CH2)r-W;
R2 is hydrogen or C1-C6 alkyl which may be substituted by one hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)r-W;
Z is C1-C6 alkoxy, -CONR4R5, -CO2R4, -CHR4OR5, -CHR4NR5R6, -COR4, -CONR4OR5 or optionally substituted aryl;
each W is independently cyano, hydroxymethyl, C2-C6 alkoxymethyl, aminomethyl, mono C1-C6 alkylaminomethyl, di C1-C6 alkylaminomethyl, carboxyl, carbamoyl or C1-C6 alkoxycarbonyl;
R4, R5 and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or an optionally substituted aryl or heterocyclic group; p is 0 to 6; and
m, n and r are each, independently, 0 to 3;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (87) - (91) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(87) A compound of the formula XIX wherein X is C1-C6 alkyl having one or two substituents selected from hydroxy, halogen, C1-C6 alkoxy, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C1-C6 alkylthio, mono C1-C6 alkylamino, di C1-C6 alkylamino, amino, cyano and azido.
(88) A compound of the formula XIX as described in paragraph (87) wherein R is methyl and the OR group is at the 2-position; Ar1 and Ar2 are each phenyl, monochlorophenyl or monofluorophenyl; Y is hydrogen or Z-(CH2)p-, wherein Z is C1-C6 alkoxy, -CONR4R5, -CO2R4, -CHR4OR5, -CHR4NR5R6, -COR4 or -CONR4OR5; and Y is at the 5- or 6-position.
(89) A compound as described in paragraph (88) wherein X is C1-C6 alkyl having one or two substituents selected from hydroxy, C1-C6 alkoxy and C1-C6 alkylthio; Ar1 and Ar2 are each phenyl; and Y is hydrogen or carboxy.
(90) A compound is described in paragraph (89) wherein X is -C(CH3)2OH, -C(OH) (CH3)CH2OH, -C(CH3)2OCH3 or
-C(CH3)2SCH2CH3.
(91) A compound as described in paragraph (90) that is selected from:
(2S,3S)-N-[5-(1-hydroxy-1-methylethyl)-2-methoxy-phenyl]methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; (2S,3S)-N-[2-methoxy-5-(1-methoxy-1-methylethyl)-phenyl]methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(3R,4S,5S,6S)-3-[5-(1-hydroxy-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethy1-1-azabicyclo[2.2.2]octan-5-carboxylic acid;
(2S,3S)-2-diphenylmethyl-N-[5-(1-hydroxy-1-hydroxymethylethyl)-2-methoxyphenyl]methyl-1-azabicyclo[2.2.2]octan-3-amine;
(3R,4S,5S,6S)-3-[5-(1-methoxy-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid;
(3R,4S,5S,6S)-3-[5-(1-hydroxy-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid; and
(3R,4S,5S,6S)-3-[5-(1-ethylthio-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
Figure imgf000070_0001
wherein X and Y are each hydrogen, halo, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl or tri C1-C6 alkylsilyl;
Ar1 and Ar2 are each aryl optionally substituted by halo;
A is -CO- or -(CH2)-;
Z-A- is at the 2 or 3 position on the quinuclidine ring;
Z is hydroxy, C1-C6 alkoxy, NR1R2 or W1-(CH2)m-CHR4-(CH2)n-NR3 wherein
R1 and R2, when taken separately, are each hydrogen or C1-C6 alkyl;
R1 and R2, when taken together with the nitrogen atom to which they are attached, represent piperidino, pyrrolidino, morpholino, thiomorpholino or piperazino;
R3 is hydrogen, C1-C6 alkyl, benzyl or -(CH2)r-W2;
R4 is hydrogen or C1-C6 alkyl which may be substituted by hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxylbenzyl, 3-indolylmethyl or -(CH2)s-W3;
R3 and R4, when taken together, represent CH2 or CH2CH2;
W1, W2 and W3 are each cyano, hydroxymethyl, C2-C6 alkoxymethyl, aminomethyl, (C1-C6 alkylamino)methyl, (di C1-C6 alkylamino)methyl, carboxyl, (C1-C6 alkyl) carbamoyl, or (di C1-C6 alkyl) carbamoyl, carbamoyl or (C1-C6 alkoxy) carbonyl; and
m, n, r and s are each 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such disorder.
As used in formula XX, the term "alkylthio" means -S- alkyl, including but not limited to methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like;
As used in formula XX, the term "alkylsulfonyl" means
-SO2-alkyl including but not limited to methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like; and
As used in formula XX, the term "aryl" means aromatic radicals including but not limited to phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl and the like. These aryl groups can be substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, phenoxy, mono- or di- C1-C6 alkylamino and the like.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (92) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(92) A compound of the formula XX that is selected from the group consisting of:
(3S,4R,5S,6S)-N-carbamoylmethyl-6-diphenylmethyl-5- (3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3S,4R,5S,6S)-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3S,4R,5S,6S)-N,N-(3-oxa-1,5-pentyIene)-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3S,4R,5S,6S)-6-diphenylmethyl-5-(3,5-dimethylbenzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylicacid;
(3S,4R,5S,6S)-N,N-diethyl-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3S,4R,5S,6S)-6-diphenylmethyl-5-(3-fluoro-5-trifluoromethylbenzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylic acid; (3S,4R,5S,6S)-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylic acid; and
(3S,4R,5S,6S)-N,N-dimethyl-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide.
This invention also relates to a method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, including a human, comprising administering to said mammal a compound of the formula
Figure imgf000073_0001
wherein Y is C2-C4 alkylene;
Z is a valence bond or C1-C6 alkylene;
R1 is phenyl, biphenyl, indanyl, naphthyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, tetrazolyl, quinolyl, phenyl C1-C6 alkyl- or benzhydryl, wherein each of the ring moieties may optionally be substituted by one or more substituents independently selected from halogen, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy and halosubstituted C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, hydroxy, cyano, amino or carboxy; and R4 represents a group of the formula (II) or (III)
Figure imgf000074_0001
Figure imgf000074_0002
wherein X1, X2 and X3 are each halo, hydrogen, nitro, C1-C6 alkyl, halosubstituted C1-C6 alkoxy, halosubstituted C1-C6 alkoxy, hydroxy, amino, C1-C6 alkylthio, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl;
Q1 and Q2 are each H2, oxygen or sulfur;
A is valence bond, methylene, oxygen, sulfur or NH; R5 and R6 are each hydrogen or C1-C6 alkyl; and
R6 is hydrogen, halogen, C1-C6 alkyl, halosubstituted C1-C6 alkyl or C1-C6 alkoxy;
provided that when Z is a valence bond, R3 must be hydrogen;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation nd breakdown of the blood aqueous barrier in a mamma., including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (93) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(93) A compound of the formula XXI that is selected from:
(2S*,3S*,4S*,5R*)-4-carboxy-3-[N-(5-isopropyl-2-methoxybenzyl)amino]-5-methyl-2-phenylpyrrolidine and
(2S*,3S*,5S*)-5-carboxy-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-2-phenylpiperidine. The term "halo", as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term "alkenyl", as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and
2-butenyl.
The term "alkoxy", as used herein, unless otherwise indicated, refers to -O-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
The term "alkylthio", as used herein, unless otherwise indicated, refers to -S-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and t-butylthio.
The term "cycloalkyl", as used herein, unless otherwise indicated, refers to cyclic hydrocarbon radicals including, but not limited to cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "one or more substituents," as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.
The term "excess lacrimation", as used herein, refers to a degree of lacrimation that is higher than the desired degree of lacrimation.
Compounds of the formulae I, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX and XXI contain chiral centers and therefore exist in different enantiomeric forms. The above definitions of these compounds include all optical isomers and all stereoisomers of such compounds, and mixtures thereof. Detailed Description of the Invention
The compounds of the formulae Ia, Ib, Ic, Id, Ie, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX and XXI may be prepared as described below. Unless otherwise indicated, in the discussion that follows, structural formulae Ia, Ib, Ic, Id, Ie, X, XI XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX and XXI and groups II, III, IV, V, VI, VII, VIII and IX are defined as above.
Compounds of the formula la and lb may be prepared as described in United States Patent Application 988,653, which was filed on December 10, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula Ic may be prepared as described in United States Patent Application 932,392, which was filed on August 19, 1992, and PCT Patent Application PCT/US 93/09407, which designates the United States and which was filed in the United States Receiving Office on October 7, 1993 and published as WO 94/13663 on June 23, 1994. These applications are incorporated herein by reference in their entirety.
Compounds of the formula Id may be prepared as described in PCT Patent Application PCT/US 92/03571, which designates the United States and which was filed in the United States Receiving Office on May 5, 1992 and published as WO 93/00331 on January 7, 1993. This application is incorporated herein by reference in its entirety.
Compounds of the formula Ie may be prepared as described in United States Patent Application 123,306, which was filed on September 17, 1993 and in PCT Patent Application PCT/IB 94/00221, which designates the United States and which was filed in the International Bureau on July 18, 1994. This application is incorporated herein by reference in its entirety.
When R3 is a group of the formula II, the starting materials of the formula NH2R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in United States Patent 5,162,339, which issued on November 11, 1992. This patent is incorporated herein by reference in its entirety.
When R3 is a group of the formula III, the starting materials of the formula NH2R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in PCT Patent Application PCT/US 91/02853, which designates the United States, was filed in the United States Receiving Office on April 25, 1991 and was published as WO 91/18899 on December 12, 1991. This application is incorporated herein by reference in its entirety.
When R3 is a group of the formula IV, V or VI, the starting materials of the formula NH2R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in PCT Patent Application PCT/US 91/03369, which designates the United States, was filed on in the United States Receiving Office May 14, 1991 and was published as WO 92/01688 on February 6, 1992. This application is incorporated herein by reference in its entirety.
When R3 is a group of the formula VII, the starting materials of the formula NH2R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in United States Patent 5,232,929, which issued on August 3, 1993, United States Patent Application 800,667, filed November 27, 1991, PCT Patent Application PCT/US 91/02541, which designates the United States, was filed in the United States Receiving Office on April 12, 1991 and was published as WO 91/18878 on December 12, 1991, and PCT Patent Application PCT/US 92/00065, which designates the United States, was filed in the United States Receiving Office on January 14, 1992 and was published as WO 92/17449 on October 15, 1992. These applications are incorporated herein by reference in their entirety. When R3 is a group of the formula VIII, the starting materials of the formula NH2R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in PCT Patent Application PCT/US 91/05776, which designates the United States, was filed in the United States Receiving Office on August 20, 1991 and was published as WO 92/06079 on April 16, 1992, United States Patent Application 800,667, filed November 27, 1991 and PCT Patent Application PCT/US 92/00065, which designates the United States, was filed in the United States Receiving Office on January 14, 1992 and was published as WO 92/17449 on October 15, 1992. These applications are incorporated herein by reference in their entirety.
When R3 is a group of the formula IX, the starting materials of the formula NH2R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic, Id and Ie may be prepared as described in United States Patent Application Serial No. 719,884, filed June 21, 1991 and PCT Patent Application PCT/US 92/04697, which designates the United States and which was filed in the United States Receiving Office on June 11, 1992 and published as WO 93/00330 on January 7, 1993. These applications are incorporated herein by reference in their entirety.
Compounds of the formula X may be prepared as described in PCT Patent Application PCT/US 92/04002, which designates the United States, was filed in the United States Receiving Office on May 19, 1992 and was published as WO 92/15585 on September 17, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XI may be prepared as described in PCT Patent App ration PCT/US 92/04697, which designates the United States, and which was filed in the United States Receiving Office on June 11, 1992 and published as WO 93/00330 on January 7, 1993. This application is incorporated herein by reference in its entirety. Compounds of the formula XII may be prepared as described in PCT Patent Application PCT/US 92/07730, which designates the United States and which was filed in the United States Receiving Office on September 18, 1992 and published as WO 93/10073 on May 27, 1993. This application is incorporated herein by reference in its entirety.
Compounds of the formula XIII may be prepared as described in PCT Patent Application PCT/US 92/06819, which designates the United States and which was filed in the United States Receiving Office on August 20, 1992 and published as WO 93/06099 on April 1, 1993. This application is incorporated herein by reference in its entirety.
Compounds of the formula XIV may be prepared as described in United States Patent Application 885,110, which was filed on May 18, 1992 and in PCT Patent Application PCT/US 93/01429, which designates the United States and which was filed in the United States Receiving Office on February 23, 1993 and published as WO 93/23380 on November 25, 1993. These applications are incorporated herein by reference in their entirety.
Compounds of the formula XV may be prepared by the procedure described in PCT Patent Application PCT/US 92/04002, which designates the United States, was filed on May 19, 1992 and published as WO 92/20676 on November 26, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XVI may be prepared as described in United States Patent Application 026,382, which was filed on April 7, 1993, and PCT Patent Application PCT/US 93/11793, which designates the United States, and which was filed on December 10 , 1993 in the U. S. Receiving Office and published as WO 94/20500 on September 15, 1994. These applications are incorporated herein by reference in their entirety.
Compounds of the formula XVII may be prepared as described in PCT Patent Application PCT/US 93/09169, which designates the United States and which was filed in the U.S. Receiving Office on September 30, 1993 and published as WO 94/10170 on May 11, 1994. This application is incorporated herein by reference in its entirety.
Compounds of the formula XVIII may be prepared as described in PCT Patent Application PCT/US 93/09168, which designates the United States and which was filed in the U.S. Receiving Office on September 30, 1993 and published as WO 94/08997 on April 28, 1994. This application is incorporated herein by reference in its entirety.
Compounds of the formula XIX may be prepared as described in PCT Patent Application PCT/JP 94/00781, which designates the United States and which was filed in the Japanese Receiving Office on May 13, 1994. This application is incorporated herein by reference in its entirety.
Compounds of the formula XX may be prepared as described in PCT Patent Application PCT/JP 94/01092, which designates the United States and was filed in the Japanese Receiving Office on July 5, 1994. This application is incorporated herein by reference in its entirety.
Compounds of the formula XXI may be prepared as described in PCT Patent Application PCT/JP 94/01514, which designates the United States and was filed in the Japanese Receiving Office on September 13, 1994. This application is incorporated herein by reference in its entirety.
The compounds of the formulae Ia, Ib, Ic, Id, Ie, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII and XIX (hereinafter referred to, collectively, as the "therapeutic agents") and the pharmaceutically acceptable salts thereof are useful as substance P receptor antagonists, i.e., they possess the ability to antagonize the effects of tachykinins at the substance P receptor site in mammals. They and other NK-1 antagonists are able to function as therapeutic agents in the treatment and prevention of disorders of the eye such as glaucoma, ocular hypertension, miosis, excess lacrimation and breakdown of the blood aqueous barrier in mammals, including humans.
The therapeutic agents that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Examples of acids that form suitable pharmaceutically acceptable salts for use in this invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a therapeutic agent from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base therapeutic agents of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
Those therapeutic agents of this invention that are also acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the therapeutic agents are those that form non-toxic base salts with the acidic therapeutic agents. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
As indicated above, therapeutic agents and their pharmaceutically acceptable salts exhibit substance P receptor binding activity. They and other NK-1 antagonists are of value in the treatment and prevention of glaucoma, ocular hypertension, miosis, excess lacrimation and breakdown of the blood aqueous barrier in mammals, including humans.
Other substance P receptor antagonists that are expected to exhibit activity for the treatment and prevention of the foregoing eye disorders in mammals, including humans, are those compounds described in the following references: European Patent Application EP 499,313, published August 19, 1992; European Patent Application EP 520,555, published December 30, 1992; European Patent Application EP 522,808, published January 13, 1993, European Patent Application EP 528,495, published February 24, 1993, PCT Patent Application WO 93/14084, published July 22, 1993, PCT Patent Application WO 93/01169, published January 21, 1993, PCT Patent Application WO 93/01165, published January 21, 1993, PCT Patent Application WO 93/01159, published January 21, 1993, PCT Patent Application WO 92/20661, published November 26, 1992, European Patent Application EP 517,589, published December 12, 1992, European Patent Application EP 428,434, published May 22, 1991, and European Patent Application EP 360,390, published March 28, 1990.
The therapeutic agents and the pharmaceutically acceptable salts thereof, as well as other NK-1 antagonists, can be administered via either the oral, topical or parenteral routes. In general, these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 21 mg per kg of body weight per day is most desirably employed. The preferred dosage for oral administration is from about 0.001 to about 5 mg per kg of body weight per day. Ointments or eyedrops will preferably contain the active agent in a concentration of about 0.01 to about 5 percent, more preferably about 1%.
Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The therapeutic agents, and their pharmaceutically acceptable salts, as well as other NK-1 antagonists may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. For parenteral administration, solutions of a therapeutic agent in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The activity of the therapeutic agents as substance P receptor antagonists may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography. The substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry. Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC50 values for each compound tested.
In this procedure, bovine caudate tissue is removed from a -70°C freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloride buffer having a pH of 7.7. The homogenate is centrifuged at 30,000 × G for a period of 20 minutes. The pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 × G for another twenty-minute period. The pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 4 μg/ml of bacitracin, 4μg/ml of leupeptin, 2μg of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
The radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 μl of the test compound made up to a concentration of 1 μM, followed by the addition of
100 μl of radioactive ligand made up to a final concentration 0.5 mM and then finally by the addition of 800 μl of the tissue preparation produced as described above. The final volume is thus 1.0 ml, and the reaction mixture is next vortexed and incubated at room temperature (ca . 20°C) for a period of 20 minutes. The tubes are then filtered using a cell harvester, and the glass fiber filters (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with the filters having previously been presoaked for a period of two hours prior to the filtering procedure. Radioactivity is then determined in a Beta counter at 53% counting efficiency, and the IC50 values are calculated by using standard statistical methods.

Claims

1. A method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, comprising administering to said mammal (a) an amount of a compound of the formula
Figure imgf000088_0001
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of ring system A; AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of AA;
AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the -CH2PR3 sidechain is attached to a carbon atom of ring AAA;
P is NR2, O, S, SO or SO2; Q is SO2, NH, or
Figure imgf000089_0001
Figure imgf000089_0002
wherein the point of attachment of said
Figure imgf000089_0003
to ring AAA is the nitrogen atom and the point of attachment to Xs is the sulfur atom;
W1 is hydrogen, halo or (C1-C6) alkyl, S-(C1-C3) alkyl, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
W2 is hydrogen, (C1-C6) alkyl, S-(C1-C3) alkyl, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
W is hydrogen, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, -S(O)v-(C1-C6) alkyl wherein v is zero, one or two, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
X1 is hydrogen, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms or (C1-C10) alkyl optionally substituted with from one to three fluorine atoms;
X2 and X3 are independently selected from hydrogen, halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)- alkylamino, di-(C1-C6) alkylamino,
Figure imgf000089_0004
(C1-C6)-
Figure imgf000090_0001
, hydroxy(C1-C4) alkyl, (C1-C4) alkoxy (C1- C4) alkyl,
Figure imgf000090_0002
and
Figure imgf000090_0003
;
Xs is a four to six membered heterocyclic ring containing from one to three heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms and halo;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazoiyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R1 is selected from amino, (C1-C6) alkylamino, di-(C1-C6) alkylamino, -S(O)v-(C1-C10) -alkyl wherein v is zero, one or two, -S(O)v-aryl wherein v is zero, one or two, -O-aryl, -SO2NR4Rs wherein each of R4 and R5 is, independently, (C1-C6) alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
Figure imgf000091_0001
,
Figure imgf000091_0002
,
Figure imgf000091_0003
Figure imgf000091_0004
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10) alkyl)2 and
Figure imgf000091_0007
; and wherein the aryl moieties of said -S(O)v-aryl, -O-aryl and
Figure imgf000091_0008
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy and halo;
or R1 is a group having the formula
or
Figure imgf000091_0005
Figure imgf000091_0006
wherein a is 0, 1 or 2 and the asterisk represents a position meta to the R2R3NCH2 side chain;
the dotted lines in formula Ib represent that one of the X-Y and Y-Z bonds may optionally be a double bond;
X is selected from =CH-, -CH2-, -O-, -S-, -SO-, -SO2-, -N(R4)-, -NH-, =N-, -CH[(C1-C6) alkyl]-, =C[(C1-C6)alkyl]-, -CH(C6H5)- and =C(C6H5)-;
Y is selected from C=O, C=NR4, C=S, =CH-, -CH2-, =C[(C1- C6)alkyl]-, -CH[(C1-C6)alkyl]-, -C(C6H5)-, -CH(C6H5)-, =N-,
-NH-, -N(R4)-, =C(halo)-, =C(OR4)-, =C(SR4)-, =C(NR4)-, -O-, -S- and SO2, wherein the phenyl moieties of said =C(C6H5)- and -CH(C6H5)- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said =[(C1-C6)alkyl]- and -CH[C1-C6)alkyl]- may optionally be substituted with from one to three fluorine atoms;
Z is selected from =CH-, -CH2-, =N-, -NH-, -S-, -N(R4)-, =C(C6H5)-, -CH(C6H5)-, =C[(C1-C6) alkyl]- and -CH[(C1-C6)alkyl]-;
or X, Y and Z, together with the two carbon atoms shared between the benzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;
R4 is (C1-C6) alkyl or phenyl;
R2 is hydrogen or -CO2(C1-C10) alkyl;
R3 is selected from
Figure imgf000093_0001
Figure imgf000094_0001
wherein R6 and R10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1-C3) alkoxy-carbonyl;
R7 is selected from (C3-C4) branched alkyl, (C5-C6) branched alkenyl, (C5-C7) cycloalkyl, and the radicals named in the definition of R6;
R8 is hydrogen or (C1-C6) alkyl;
R9 and R19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R9 and R19 may optionally be substituted with from one to three substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
Y1 is (CH2), wherein 1 is an integer from one to three, or Y1 is a group of the formula
Figure imgf000095_0001
;
Z1 is oxygen, sulfur, amino, (C1-C3) alkylamino or (CH2)n wherein n is zero, one or two;
x is an integer from zero to four;
y is an integer from zero to four;
z is an integer from one to six, wherein the ring containing (CH2)zmay contain from zero to three double bonds, and one of the carbons of (CH2)z may optionally be replaced by oxygen, sulfur or nitrogen;
o is two or three;
p is zero or one; r is one, two or three;
R11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
X4 is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R14, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R15;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R17;
R12 is a radical selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6) alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1- C6)alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6)-alkylamino,
Figure imgf000097_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1-C6) alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), cyano, hydroxy-(C1- C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6) alkylamino, d
, ( ,
Figure imgf000097_0001
Figure imgf000098_0001
,
Figure imgf000098_0002
, and the radicals set forth in the definition of R12;
R16 is
Figure imgf000098_0003
, NHCH2R18, SO2R18, GR20 CO2H or one of the radicals set forth in any of the definitions of R12, R14 and R15;
R17 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R12, R14 and R15; and
R18 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
G is selected from the group consisting of CH2, nitrogen, oxygen, sulfur and carbonyl;
R20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
Figure imgf000098_0004
Figure imgf000098_0005
wherein B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH2)n or (CH2)n+1 may be optionally substituted with (C1-C6) alkyl or (C2-C6) spiroalkyl, and either any two of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbons of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
with the proviso that (a) when m is O, one of R16 and R17 is absent and the other is hydrogen, (b) when R3 is a group of the formula VIII, R14 and R15 cannot be attached to the same carbon atom, (c) when R14 and R15 are attached to the same carbon atom, then either each of R14 and R15 is independently selected from hydrogen, fluoro, (C1-C6) alkyl, hydroxy- (C1-C6) alkyl and (C1-C6) alkoxy-(C1-C6) alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3-C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R12 and R13 cannot both be hydrogen; (e) when R14 or R15 is attached to a carbon atom of X4 or (CH2)y that is adjacent to the ring nitrogen, then R14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom; and (f) neither R14, R15, R16 nor R17 can form a ring with R13;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(b) an amount of a compound having the formula
Figure imgf000099_0001
wherein W is Y or X(CH2)n;
Y is optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl or optionally substituted (C3-C8) cycloalkyl;
X is optionally substituted (C1-C6) alkoxy, hydroxy,
CONR1R2, CO2R1, CHR1OR2, CHR1NR2R3, COR1, CONNOR2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl. oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
Ar1, Ar2 and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and R1, R2 and R3 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C8) cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C1-C5) heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;
and wherein the substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl and trifluoromethoxy;
and wherein the substituents on the foregoing substituted (C1-C5) heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C1-C4) alkyl when attached to a ring sulfur atom, and are independently selected from oxygen and (C1-C4) alkyl when attached to a ring nitrogen atom;
and wherein the substituents on said substituted Ar1 groups are independently selected from (C1-C6) alkyl optionally substituted with from one to three halo groups, (C1-C6)alkox optionally substituted with from one to three halo group., (C1-C6) alkylsulfinyl, (C2-C6) alkenyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6)alkylsulfonylamino, and di-(C1-C6) alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C1-C6) alkylsulfonyl, or (C1-C6) alkylsulfinyl group; and wherein the substituents on said substituted Ar2 and Ar3 groups are independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, di-(C1-C4) alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C1-C4) alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(c) A method of treating or preventing emesis in a mammal, comprising administering to said mammal an amount of a compound having the formula
Figure imgf000101_0001
wherein R1 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, amino, trihaloalkoxy (e.g., trifluoromethoxy),
Figure imgf000102_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy substituted with from one to three fluorine atoms, amino, phenyl, trihaloalkoxy,
Figure imgf000102_0001
Figure imgf000103_0004
Figure imgf000103_0005
and -
Figure imgf000103_0006
one of R5 and R6 is hydrogen and the othar is selected from hydroxymethyl, hydrogen, (C1-C3) alkyl, (C1-C8)acyloxy(C1-C3) alkyl, (C1-C8) alkoxymethyl and benzyloxymethyl;
R7 and R8 are independently selected from hydrogen, (C1- C3) alkyl and phenyl;
R9 is selected from methyl, hydroxymethyl,
Figure imgf000103_0003
, R14R15NCO2CH2-, R16OCO2CH2-, (C1-C4) alkyl-CO2CH2-, -CONR17R18, R17R18NCO2-, R19OCO2-, C6H5CH2CO2CH2-, C6H5CO2CH2-, (C1-C4) alkyl- CH(OH)-, C6H5CH(OH)-, C6H5CH2CH(OH)-, CH2halo, R20SO2OCH2, -CO2R16 and R21CO2-;
R10 and R11 are independently selected from hydrogen, (C1- C3) alkyl and phenyl;
R12 is hydrogen, benzyl or a group of the formula
Figure imgf000103_0002
wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, where in both carbon atoms of such bond are bonded to each other Λnd to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R23;
R13, R14, R15, R16, R17, R18, R19, R20, R21 and R24 are independently selected from hydrogen, (C-C3) alkyl and phenyl;
R22 and R23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy (C1-C6) alkyl, (C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy, (C1-C6)-
Figure imgf000103_0001
Figure imgf000104_0003
Figure imgf000104_0004
(C1-C6) straight or branched alkyl, (C3-
Figure imgf000104_0005
C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2- C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-CC6) alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1- C6) alkoxy optionally substituted with from one to three fluorine atoms,
trifluoromethyl, amino, (C1-C6)-alkylamino,
Figure imgf000104_0002
Figure imgf000104_0001
wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached form a second pyrrolidine ring; with the proviso that when
R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R12 is absent or R12 is present and the nitrogen of the second pyrrolidine ring is positively charged;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(d) an amount of a compound of the formula
Figure imgf000105_0002
wherein R1 is hydrogen, (C1-C8) alkyl, a saturated (C6-C10) carbocyclic ring system containing two fused rings, a saturated (C6-C10) carbocyclic bridged ring system containing two rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C8) alkoxy optionally substituted with from one to three fluorine atoms;
R2 is hydrogen, benzyl or a group of the formula
Figure imgf000105_0001
wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R9; R8 and R9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C1-C6) alkyl,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
Figure imgf000106_0001
Figure imgf000106_0002
straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2- C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1- C6)alkoxy optionally substituted with from one to three fluorine atoms,
Figure imgf000106_0003
Figure imgf000107_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
R4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, phenyl, a
Figure imgf000107_0001
R3 is hydrogen, (C3-C8) cycloalkyl, (C1-C6) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R5 is hydrogen, (C1-C6) alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R6 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C1-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, trifluoromethyl, amino, trihaloalkoxy
Figure imgf000108_0001
and
Figure imgf000109_0001
Figure imgf000109_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R12 is hydrogen, (C1-C3) alkyl or phenyl;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder;
(e) an amount of a compound of the formula
Figure imgf000109_0003
wherein R1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
R2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
R3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(f) an amount of a compound of the formula
Figure imgf000110_0001
wherein m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8;
w is an integer from 0 to 2;
y is an integer from 1 to 4;
z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH2)z may optionally be substituted with
R4;
R1 is hydrogen or (C1-C8) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
R2 is a group selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, amino,
Figure imgf000111_0001
R5 is hydrogen, phenyl or (C1-C6) alkyl;
or R2 and R5, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
R3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, phenyl,
Figure imgf000112_0003
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), nitrile,
Figure imgf000112_0001
R6 is
Figure imgf000112_0002
, NHCH2R9, NHSO2R9 or one of the groups set forth in any of the definitions of R2, and R4;
R8 is oximino (=NOH) or one of the groups set forth in any of the definitions of R2, and R4;
R9 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
with the proviso that (a) when m is O, R8 is absent and R6 is hydrogen, (b) neither R4, R6, nor R8 can form, together with the carbon to which it is attached, a ring with R5, and (c) the sum of y and z must be less than 7;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(g) an amount of a compound of the formula
Figure imgf000113_0003
wherein X1 is (C1-C5) alkoxy or halosubstituted (C1-C5) alkoxy;
X2 is hydrogen, halogen, (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C3) alkynyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, halosubstituted (C1- C5) alkyl, halosubstituted (C1-C5) alkoxy, (C1-C5) alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C1-C5)alkylsulfonylamino (which may be substituted by halogen),
Figure imgf000113_0002
(which may be substituted by halogen in the alkylsulfonyl moiety), (C1- C5) alkanoylamino (which may be substituted by halogen) or
Figure imgf000113_0001
(which may be substituted by halogen in the alkanoyl moiety);
Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
A is Y-(CH2)m-CH(R2)-(CH2)n-NR1-;
Rl is hydrogen, (C1-C5) alkyl, benzyl or -(CH2)p-Y;
R2 is hydrogen, (C1-C5) alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)p-Y;
Y is -CN, -CH2Z or -COZ; Z is hydroxy, amino, (C1-C5) alkoxy, (C1-C3) alkylamino or dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety;
m, n and p are each, independently, 0, 1, 2 or 3; and
R1 and R2 may be connected to form a ring;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(h) an amount of a compound of the formula
Figure imgf000114_0005
wherein R1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6) -alkylamino, di-(C1-C6) alkylamino,
Figure imgf000114_0001
hydroxy(C1-C4) alkyl,
Figure imgf000114_0002
Figure imgf000114_0003
Figure imgf000114_0004
, (C1-C4) alkoxy (C1-C4) alkyl, -S(O)v- (C1-C10) -alkyl wherein v is zero, one or two, -S(O)v-aryl wherein v is zero, one or two, -O-aryl, -SO2NR4R5 wherein each of R4 and R5 is, independently, (C1-C6) alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
Figure imgf000115_0003
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10)alkyl)2 and
Figure imgf000115_0001
and wherein the aryl moieties of said -S(O)v-aryl, -O-aryl and
Figure imgf000115_0002
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy and halo;
or R1 is phenyl substituted with a group having the formula
or
Figure imgf000115_0004
Figure imgf000115_0005
wherein a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R1 ;
R2 is selected from (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituents, independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino., hydroxy-(C1-C6) alkyl, (C1-C6) alkoxy- (C1-C6) alkyl, (C1-C6)-alkylamino,
Figure imgf000116_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
m is an integer from 0 to 8 , and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R4;
R3 is selected from , NHCH2R8, SO2R8, AR9, CO2H and
Figure imgf000116_0001
the radicals set forth in the definitions of R2, R6 and R7;
A is CH2, nitrogen, oxygen, sulfur or carbonyl;
R8 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
R4 is selected from oximino (=NOH) and the radicals set forth in the definitions of R2, R6 and R7; R9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl,
2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae and
Figure imgf000117_0002
Figure imgf000117_0003
wherein B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH2)n and (CH2)n+1 may be optionally substituted with (C1-C6) alkyl or (C2-C6) spiroalkyl; and either any one pair of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
X is (CH2)q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R6, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R7;
R6 and R7 are independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), cyano, hydroxy-(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6)alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
Figure imgf000117_0001
Figure imgf000118_0002
set forth in the definition of R2; and
Y is (CH2)z wherein z is zero or one;
with the proviso that: (a) when A is -(CH2)- or carbonyl, R9 cannot be furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl or thienyl; (b) when m is zero, one of R3 and R4 is absent and the other is hydrogen; and (c) when R6 or R7 is attached to a carbon atom of X that is adjacent to the ring nitrogen, then R6 or R7, respectively, must be a substituent wherein the point of attachment is a carbon atom;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(i) an amount of a compound of the formula
Figure imgf000118_0001
XVI I
wherein Ar1 and Ar2 are each independently aryl or substituted aryl;
R1 is alkyl having from 1 to 6 carbon atoms; R2 is hydrogen or alkyl having from 1 to 6 carbon atoms; and either X and Y are taken separately and they are each, independently, hydrogen, dialkylphosphoryl having from 2 to 12 carbon atoms, alkyl having from 1 to 6 carbon atoms; or X and Y are taken together and they represent a hydrocarbon chain having 3, 4, or 5 carbon atoms, optionally containing up to 2 double bonds and optionally having 1 or 2 substituents selected from oxo, hydroxy and alkyl having from 1 to 6 carbon atoms;
provided that when X and Y are taken together they are attached to adjacent carbon atoms; and
provided that if either X or Y is hydrogen, then the other one must be alkenyl or alkynyl;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder; or
(j) an amount of a compound of the formula
Figure imgf000119_0001
wherein Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
X is -CONR3R4, -CO2R3, CH2OR3, -CH2NR3R4 or -CONR3OR4;
R1, R3 and R4 are each, independently, hydrogen or alkyl having 1 to 4 carbon atoms;
R2 is alkyl having 1 to 4 carbon atoms;
Y is alkylsulfonyl having 1 to 4 carbon atoms, N-alkyl-N-alkanoylamino (which may be substituted by halogen in the alkanoyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkanoyl moieties, N-alkyl-N-alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkyl sulfonyl moieties, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, halosubstituted alkyl having 1 to 4 carbon atoms, alkylamino having 1 to 4 carbon atoms, alkanoylamino (which may be substituted by halogen) having 1 to 4 carbon atoms or alkylsulfonylamino (which may be substituted by halogen) having 1 to 4 carbon atoms;
or a pharmaceutically acceptable salt thereof that is effective in treating or preventing disorder; or
(k) an amount of a compound of the formula
Figure imgf000120_0001
wherein R is C1-C6 alkyl;
X is C1-C6 alkyl having one or more substituents bonded through a heteroatom;
Ar1 and Ar2 are each, independently, aryl optionally substituted by one C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, phenoxy, mono C1-C6 alkylamino, di C1-C6 alkylamino, halosubstituted C1-C6 alkyl, or halosubstituted C1-C6 alkoxy;
Y is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Z-(CH2)p-, or W-(CH2)m-CHR2-(CH2)n-NR1CO- wherein Y is at the 4-, 5- or 6-position on the quinuclidine ring; R1 is hydrogen, C1-C6 alkyl, benzyl or -(CH2)r-W;
R2 is hydrogen or C1-C6 alkyl which may be substituted by one hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)r-W;
Z is C1-C6 alkoxy, -CONR4R5, -CO2R4, -CHR4OR5, -CHR4NR5R6, -COR4, -CONR4OR5 or optionally substituted aryl;
each W is independently cyano, hydroxymethyl, C2-C6 alkoxymethyl, aminomethyl, mono C1-C6 alkylaminomethyl, di C1-C6 alkylaminomethyl, carboxyl, carbamoyl or C1-C6 alkoxycarbonyl;
R4, R5 and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or an optionally substituted aryl or heterocyclic group;
p is 0 to 6; and
m, n and r are each, independently, 0 to 3;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorders; or
(1) an amount of a compound of the formula
Figure imgf000121_0001
wherein X and Y are each hydrogen, halo, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl or tri C1-C6 alkylsilyl;
Ar1 and Ar2 are each aryl optionally substituted by halo;
A is -CO- or -(CH2)-; Z-A- is at the 2 or 3 position on the quinuclidine ring;
Z is hydroxy, C1-C6 alkoxy, NR1R2 or W1-(CH2)m-CHR4-(CH2)n-NR3 wherein
R1 and R2, when taken separately, are each hydrogen or C1-C6 alkyl;
R1 and R2, when taken together with the nitrogen atom to which they are attached, represent piperidino, pyrrolidino, morpholino, thiomorpholino or piperazino;
R3 is hydrogen, C1-C6 alkyl, benzyl or -(CH2)r-W2;
R4 is hydrogen or C1-C6 alkyl which may be substituted by hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxylbenzyl, 3-indolylmethyl or -(CH2)s-W3;
R3 and R4, when taken together, represent CH2 or CH2CH2;
W1, W2 and W3 are each cyano, hydroxymethyl, C2-C6 alkoxymethyl, aminomethyl, (C1-C6 alkylamino)methyl, (di C1-C6 alkylamino)methyl, carboxyl, (C1-C6 alkyl) carbamoyl, or (di C1-C6 alkyl) carbamoyl, carbamoyl or (C1-C6 alkoxy) carbonyl; and
m, n, r and s are each 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such disorder; or
(m) an amount of a compound of the formula
Figure imgf000122_0001
wherein Y is C2-C4 alkylene;
Z is a valence bond or C1-C6 alkylene; R1 is phenyl, biphenyl, indanyl, naphthyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, tetrazolyl, quinolyl, phenyl C1-C6 alkyl- or benzhydryl, wherein each of the ring moieties may optionally be substituted by one or more substituents independently selected from halogen, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy and halosubstituted C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, hydroxy, cyano, amino or carboxy; and
R4 represents a group of the formula (II) or (III)
Figure imgf000123_0001
wherein X1, X2 and X3 are each halo, hydrogen, nitro, C1-C6 alkyl, halosubstituted C1-C6 alkoxy, halosubstituted C1-C6 alkoxy, hydroxy, amino, C1-C6 alkylthio, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl;
Q1 and Q2 are each H2, oxygen or sulfur;
A is valence bond, methylene, oxygen, sulfur or NH; R5 and R6 are each hydrogen or C1-C6 alkyl; and
R6 is hydrogen, halogen, C1-C6 alkyl, halosubstituted C1-C6 alkyl or C1-C6 alkoxy;
provided that when Z is a valence bond, R3 must be hydrogen;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
2. A method according to claim 1, wherein the compound administered is a compound of the formula
Figure imgf000124_0001
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of ring system A; AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of AA;
AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the -CH2PR3 sidechain is attached to a carbon atom of ring AAA;
P is NR2, O, S, SO or SO2; Q is SO2, NH,
Figure imgf000125_0004
or
Figure imgf000125_0002
wherein the point of attachment of said to
Figure imgf000125_0003
ring AAA is the nitrogen atom and the point of attachment to X5 is the sulfur atom;
W1 is hydrogen, halo or (C1-C6) alkyl, S-(C1-C3) alkyl, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
W2 is hydrogen, (C1-C6) alkyl, S-(C1-C3) alkyl, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
W is hydrogen, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, -S(O)v-(C1-C6) alkyl wherein v is zero, one or two, halo or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
X1 is hydrogen, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms or (C1-C10) alkyl optionally substituted with from one to three fluorine atoms;
X2 and X3 are independently selected from hydrogen, halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)- alkylamino, di-(C1-C6) alkylamino, (C1-C6)
Figure imgf000125_0001
Figure imgf000126_0001
, hydroxy(C1-C4) alkyl, (C1-C4) alkoxy(C1- C4) alkyl,
Figure imgf000126_0003
and
Figure imgf000126_0002
X5 is a four to six membered heterocyclic ring containing from one to three heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms and halo;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazoiyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R1 is selected from amino, (C1-C6) alkylamino, di-(C1- C6) alkylamino, -S(O)v-(C1-C10)-alkyl wherein v is zero, one or two, -S(O)v-aryl wherein v is zero, one or two, -O-aryl, -SO2NR4R5 wherein each of R4 and R5 is, independently, (C1-C6) alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
Figure imgf000127_0002
Figure imgf000127_0003
Figure imgf000127_0004
Figure imgf000127_0005
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10)alkyl)2 and and
Figure imgf000127_0006
wherein the aryl moieties of said -S(O)v-aryl, -O-aryl and
Figure imgf000127_0001
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy and halo;
or R1 is a group having the formula
Figure imgf000127_0007
wherein a is 0, l or 2 and the asterisk represents a position meta to the R2R3NCH2 side chain;
the dotted lines in formula lb represent that one of the X-Y and Y-Z bonds may optionally be a double bond;
X is selected from =CH-, -CH2-, -O-, -S-, -SO-, -SO2-, -N(R4)-, -NH-, =N-, -CH[(C1-C6)alkyl]-, =C[(C1-C6)alkyl]-, -CH(C6H5)- and =C(C6H5)-;
Y is selected from C=O, C=NR4, C=S, =CH-, -CH2-, =C[(C1-C6)alkyl]-, -CH[(C1-C6)alkyl]-, =C(C6H5)-, -CH(C6H5)-, =N-,
-NH-, -N(R4)-, =C(halo)-, =C(OR4)-, =C(SR4)-, =-C(NR4)-, -O-, -S- and SO2, wherein the phenyl moieties of said =C(C6H5)- and -CH(C6H5)- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said =[(C1-C6)alkyl]- and -CH[C1-C6)alkyl]- may optionally be substituted with from one to three fluorine atoms;
Z is selected from =CH-, -CH2-, =N-, -NH-, -S-, -N(R4)-, =C(C6H5)-, -CH(C6H5)-, =C[(C1-C6) alkyl]- and -CH[(C1-C6)alkyl]-;
or X, Y and Z, together with the two carbon atoms shared between the benzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;
R4 is (C1-C6) alkyl or phenyl;
R2 is hydrogen or -CO2(C1-C10) alkyl;
R3 is selected from
Figure imgf000129_0001
Figure imgf000130_0001
wherein R6 and R10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1-C3) alkoxy-carbonyl;
R7 is selected from (C3-C4) branched alkyl, (C3-C6) branched alkenyl, (C5-C7) cycloalkyl, and the radicals named in the definition of R6;
R8 is hydrogen or (C1-C6) alkyl;
R9 and R19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R9 and R19 may optionally be substituted with from one to three substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
Y1 is (CH2), wherein 1 is an integer from one to three, or Y1 is a group of the formula
Figure imgf000131_0001
;
Z1 is oxygen, sulfur, amino, (C1-C3) alkylamino or (CH2)n wherein n is zero, one or two;
x is an integer from zero to four;
y is an integer from zero to four;
z is an integer from one to six, wherein the ring containing (CH2)z may contain from zero to three double bonds, and one of the carbons of (CH2)z may optionally be replaced by oxygen, sulfur or nitrogen;
o is two or three;
p is zero or one; r is one, two or three;
R11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
X4 is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R14, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R15;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carcon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R17;
R12 is a radical selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6) alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1- C6)alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6)-alkylamino, (
(
(
d
(
Figure imgf000133_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1-C6) alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), cyano, hydroxy-(C1- C6)alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6)alkylamino,
Figure imgf000133_0001
Figure imgf000134_0002
and the radicals set forth in the definition of R12;
O
R16 is NHCR18, NHCH2R18, SO2R18, GR20 CO2H or one of the radicals set forth in any of the definitions of R12, R14 and R1S;
R17 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R12, R14 and R15; and
R18 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
G is selected from the group consisting of CH2, nitrogen, oxygen, sulfur and carbonyl;
R20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
Figure imgf000134_0001
wherein B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH2)n or (CH2)n+1 may be optionally substituted with (C1-C6) alkyl or (C2-C6) spiroalkyl, and either any two of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbons of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
with the proviso that (a) when m is O, one of R16 and R17 is absent and the other is hydrogen, (b) when R3 is a group of the formula VIII, R14 and R15 cannot be attached to the same carbon atom, (c) when R14 and R15 are attached to the same carbon atom, then either each of R14 and R15 is independently selected from hydrogen, fluoro, (C1-C6) alkyl, hydroxy- (C1-C6) alkyl and (C1-C6) alkoxy- (C1-C6) alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3-C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R12 and R13 cannot both be hydrogen; (e) when R14 or R15 is attached to a carbon atom of X4 or (CH2)y that is adjacent to the ring nitrogen, then R14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom; and (f) neither R14, R15, R16 nor R17 can form a ring with R13;
or a pharmaceutically acceptable salt thereof.
3. A method according to claim 1, wherein the compound administered is a compound having the formula
Figure imgf000135_0001
wherein W is Y or X(CH2)n;
Y is optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl or optionally substituted (C3-C8) cycloalkyl;
X is optionally substituted (C1-C6) alkoxy, hydroxy,
CONR1R2, CO2R1, CHR1OR2, CHR1NR2R3, COR1, CONR1OR2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl. oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
Ar1, Ar2 and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and R1, R2 and R3 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C8) cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C1-C3) heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;
and wherein the substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl and trifluoromethoxy;
and wherein the substituents on the foregoing substituted (C1-C5) heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C1-C4) alkyl when attached to a ring sulfur atom, and are independently selected from oxygen and (C1-C4) alkyl when attached to a ring nitrogen atom;
and wherein the substituents on said substituted Ar1 groups are independently selected from (C1-C6) alkyl optionally substituted with from one to three halo groups, (C1-C6) alkoxy optionally substituted with from one to three halo groups, (C1-C6) alkylsulfinyl, (C2-C6) alkenyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonylamino, and di-(C1-C6) alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C1-C6) alkylsulfonyl, or (C1-C6) alkylsulfinyl group; and wherein the substituents on said substituted Ar2 and Ar3 groups are independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, di-(C1-C4) alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C1-C4) alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
or a pharmaceutically acceptable salt of such compound.
4. A method according to claim 1, wherein the compound administered is a compound having the formula
Figure imgf000137_0002
wherein R1 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, amino, trihaloalkoxy (e.g., trifluoromethoxy),
(
Figure imgf000137_0001
Figure imgf000138_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy substituted with from one to three fluorine atoms, amino, phenyl, trihaloalkoxy,
Figure imgf000138_0001
one of R5 and R6 is hydrogen and the other is selected from hydroxymethyl, hydrogen, (C1-C3) alkyl, (C1-C8) acyloxy- (C1-C3) alkyl, (C1-C8) alkoxymethyl and benzyloxymethyl; R7 and R8 are independently selected from hydrogen, (C1- C3) alkyl and phenyl;
R9 is selected from methyl, hydroxymethyl, R14R15N
Figure imgf000139_0004
CO2CH2- , R16OCO2CH2- , (C1-C4) alkyl-CO2CH2- , -CONR17R18,
R17R18NCO2- , R19OCO2- , C6H5CH2CO2CH2- , C6H5CO2CH2- , (C1-C4) alkyl- CH (OH) - , C6H5CH (OH) - , C6H5CH2CH (OH) - , CH2halo, R20SO2OCH2 , -CO2R16 and R21CO2-;
R10 and R11 are independently selected from hydrogen, (C1- C3) alkyl and phenyl;
R12 is hydrogen, benzyl or a group of the formula
Figure imgf000139_0002
wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R23;
R13, R14, R1S, R16, R17, R18, R19, R20, R21 and R24 are independently selected from hydrogen, (C1-C3) alkyl and phenyl;
R22 and R23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C1-C6) alkyl, (C1- C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy, (C1-C6)- a
Figure imgf000139_0001
Figure imgf000139_0003
(C1-C6) straight or branched alkyl, (C3- C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2- C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1- C6) alkoxy optionally substituted with from one to three fluorine atoms, t
Figure imgf000140_0001
wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached form a second pyrrolidine ring; with the proviso that when R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R12 is absent or R12 is present and the nitrogen of the second pyrrolidine ring is positively charged; or a pharmaceutically acceptable salt of such compound.
5. A method according to claim 1, wherein the compound administered is a compound of the formula
Figure imgf000141_0001
wherein R1 is hydrogen, (C1-C8) alkyl, a saturated (C6-C10) carbocyclic ring system containing two fused rings, a saturated (C6-C10) carbocyclic bridged ring system containing two rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C8) alkoxy optionally substituted with from one to three fluorine atoms;
R2 is hydrogen, benzyl or a group of the formula
Figure imgf000141_0002
wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R9;
R8 and R9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy (C1-C6) alkyl,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
Figure imgf000141_0003
Figure imgf000142_0003
Figure imgf000142_0004
(C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2- C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl- (C2-C6) alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1- C6) alkoxy optionally substituted with from one to three fluorine atoms,
O
t j
Figure imgf000142_0001
Figure imgf000142_0002
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; or R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
R4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, phenyl,
Figure imgf000143_0001
R3 is hydrogen, (C3-C8) cycloalkyl, (C1-C6) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C1- C6) alkyl optionally substituted with from one to three fluorine atoms, and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R5 is hydrogen, (C1-C6) alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R6 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy, trifluoromethyl, amino, trihaloalkoxy
Figure imgf000144_0001
Figure imgf000145_0001
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R12 is hydrogen, (C1-C3) alkyl or phenyl;
or a pharmaceutically acceptable salt of such compound.
6. A method according to claim 1, wherein the compound administered is a compound of the formula
Figure imgf000145_0002
wherein R1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
R2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
R3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
or a pharmaceutically acceptable salt of such compound.
7. A method according to claim 1, wherein the compound administered is a compound of the formula
Figure imgf000146_0001
wherein m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8;
w is an integer from 0 to 2;
y is an integer from 1 to 4;
z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH2)z may optionally be substituted with
R4;
R1 is hydrogen or (C1-C8) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
R2 is a group selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, amino,
(
(
Figure imgf000147_0001
R5 is hydrogen, phenyl or (C1-C6) alkyl;
or R2 and R5, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
R3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, phenyl,
Figure imgf000148_0001
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), nitrile,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
(
(
Figure imgf000148_0002
(
set forth in the definition of R2; R6 is
Figure imgf000148_0003
NHCH2R9, NHSO2R9 or one of the groups set forth in any of the definitions of R2, and R4;
R8 is oximino (=NOH) or one of the groups set forth in any of the definitions of R2, and R4;
R9 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
with the proviso that (a) when m is O, R8 is absent and R6 is hydrogen, (b) neither R4, R6, nor R8 can form, together with the carbon to which it is attached, a ring with R5, and (c) the sum of y and z must be less than 7;
or a pharmaceutically acceptable salt thereof.
8. A method according to claim 1, wherein the compound administered is a compound of the formula
Figure imgf000149_0003
wherein X1 is (C1-C5) alkoxy or halosubstituted (C1-C5) alkoxy;
X2 is hydrogen, halogen, (C1-C5) alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C1-C3) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, halosubstituted (C1-C5) alkyl, halosubstituted (C1-C3) alkoxy, (C1-C5) alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C1-C5)alkylsulfonylamino (which may bs substituted by halogen),
Figure imgf000149_0001
(which may be substituted by halogen in the alkylsulfonyl moiety), (C1-C5) alkanoylamino (which may be substituted by halogen) or
Figure imgf000149_0002
(which may be substituted by halogen in the alkanoyl moiety);
Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
A is Y-(CH2)m-CH(R2)-(CH2)n-NR1-;
R1 is hydrogen, (C1-C5) alkyl, benzyl or -(CH2)p-Y;
R2 is hydrogen, (C1-C5) alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)p-Y;
Y is -CN, -CH2Z or -COZ; Z is hydroxy, amino, (C1-C5) alkoxy, (C1-C5) alkylamino or dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety;
m, n and p are each, independently, 0, 1, 2 or 3; and
R1 and R2 may be connected to form a ring;
or a pharmaceutically acceptable salt thereof.
9. A method according to claim 1, wherein the compound administered is a compound of the formula
Figure imgf000150_0001
wherein R1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)-alkylamino, di-(C1-C6) alkylamino,
Figure imgf000150_0002
Figure imgf000150_0003
, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, -S(O)v-
Figure imgf000150_0004
Figure imgf000150_0005
(C1-C10)-alkyl wherein v is zero, one or two, -S(O)v-aryl wherein v is zero, one or two, -O-aryl, -SO2NR4R5 wherein each of R4 and R5 is, independently, (C1-C6) alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
Figure imgf000151_0002
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, -N(SO2-(C1-C10)alkyl)2 and
Figure imgf000151_0001
and wherein the aryl moieties of said -S(O)v-aryl, -O-aryl and
Figure imgf000151_0003
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4) alkyl, (C1- C4) alkoxy and halo;
or R1 is phenyl substituted with a group having the formula
or
Figure imgf000151_0004
Figure imgf000151_0005
wherein a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R1;
R2 is selected from (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituents, independently selected from halo, nitro. (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1- C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, (C1-C6)-alkylamino,
Figure imgf000152_0001
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
m is an integer from 0 to 8, and any one of the carbon- carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R4;
R3 is selected from
Figure imgf000152_0002
NHCH2R8, SO2R8, AR9, CO2H and the radicals set forth in the definitions of R2, R6 and R7;
A is CH2, nitrogen, oxygen, sulfur or carbonyl;
R8 is (C1-C6) alkyl, hydrogen, phenyl or phenyl (C1-C6) alkyl;
R4 is selected from oximino (=NOH) and the radicals set forth in the definitions of R2, R6 and R7; R9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl,
2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae
Figure imgf000153_0002
wherein B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH2)n and (CH2)n+1 may be optionally substituted with (C1-C6) alkyl or (C2-C6) spiroalkyl; and either any one pair of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
X is (CH2)q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R6, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R7;
R6 and R7 are independently selected from hydrogen, hydroxy, halo, amino, oxo (=O), cyano, hydroxy-(C1-C6) alkyl, (C1-C6) alkoxy- (C1-C6) alkyl, (C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkoxy,
Figure imgf000153_0001
Figure imgf000154_0001
set forth in the definition of R2; and
Y is (CH2)z wherein z is zero or one;
with the proviso that: (a) when A is -(CH2)- or carbonyl, R9 cannot be furyl, pyridyl, isothiazoiyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl or thienyl; (b) when m is zero, one of R3 and R4 is absent and the other is hydrogen; and (c) when R6 or R7 is attached to a carbon atom of X that is adjacent to the ring nitrogen, then R6 or R7, respectively, must be a substituent wherein the point of attachment is a carbon atom;
or a pharmaceutically acceptable salt of such compound.
10. A method according to claim 2, wherein the compound administered to said mammal is selected from the group consisting of:
(2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3- trifluoromethoxyphenyl)piperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino- 2-phenyl-piperidine;
(2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2- phenyl-piperidine;
(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2- phenylpiperidine;
(2S,3S)-3(-5-tert-butyl-2-trifluoromethoxybenzyl)amino- 2-phenylpiperidine;
2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxyphenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)- benzyl]amino-2-phenylpiperidine; (2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)-aminopiperidine;
(2S,3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidine;
and the pharmaceutically acceptable salts of the foregoing compounds.
11. A method according to claim 2, wherein the compound administered to said mammal is selected from the group consisting of:
cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;
cis-3-(2-trifluoromethylbenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-methyIpheny1)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methylphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-thienyl)-piperidine; cis-3-(2-methoxybenzylamino)-2-phenylazacyclo-heptane;
3-(2-methoxybenzylamino)-4-methyl-2-phenylpiperidine;
3-(2-methoxybenzylamino)-5-methyl-2-phenylpiperidine;
3-(2-methoxybenzylamino)-6-methyl-2-phenylpiperidine; (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-carboethoxypent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(6-hydroxy-hex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5,6-dihydroxyhex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxy-5-methylbenzylamir.o)-2-phenylpiperidine;
(2S,3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenylpiperidine;
(2S,3S)-3-(2-methoxybenzylamino)-1-(5-N-methylcarboxamidopent-1-yl)-2-phenylpiperidine;
(2S,3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine; (2S,3S)-1-(5-aminopent-1-yl)-3-(2-methoxybenzylamino)- 2-phenylpiperidine;
(2S,3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;
cis-3-(3,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(4,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2,5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-2-phenylpiperidine;
cis-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1-yl)-2-phenylpiperidine;
cis-1-(5,6-dihydroxyhex-1-yl)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;
cis-2-phenyl-3-[-2(prop-2-yloxy)benzylamino]piperidine; cis-3-(2,5-dimethoxybenzyl)amino-2-(3-methoxyphenyl)piperidine hydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-methoxyphenyl)piperidine dihydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-chlorophenyl)piperidine dihydrochloride;
3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;
(2S,3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-pheny1¬piperidine; (2S,3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenylpiperidine;
and the pharmaceutically acceptable salts of the foregoing compounds.
12. A method according to claim 2, wherein the compound administered to said mammal is selected from the group consisting of:
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;
N-(4,5-dimethylthiazol-2-yl)-N-[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-yl-aminomethyl)phenyl]-methanesulfonamide;
{5-[(4,5-dimethylthiazol-2-yl)methylamino]-2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-yl)amine;
{5-(4,5-dimethylthiazol-2-ylamino)-2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-ylamine;
4,5-dimethylthiazole-2-sulfonic acid methyl-[3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)-4-trifluoromethoxyphenyl]-amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3- ((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide; and the pharmaceutically acceptable salts of the foregoing compounds.
13. A method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, comprising administering to said mammal an amount of a compound selected from the group consisting of:
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S,3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine.
and the pharmaceutically acceptable salts of the foregoing compounds, that is effective in treating or preventing such disorder.
14. A method according to claim 3, wherein the compound administered to said mammal is selected from the group consisting of:
(3R,4S,5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6- diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid; (3R,4S,5S,6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylie acid;
(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo-[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-N-methyl-methanesulfonylamino-2-methoxy-benzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsuIfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)- 6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylie acid;
(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid; (3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-N-methyl-methanesulfonylamino-2-methoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
and the pharmaceutically acceptable salts of the foregoing compounds.
15. A method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, comprising administering to said mammal an amount of a compound that is an NK-1 receptor antagonist, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
16. A method of treating or preventing a disorder of the eye selected from glaucoma, ocular hypertension, miosis, hyperemia, excess lacrimation and breakdown of the blood aqueous barrier in a mammal, comprising administering to said mammal an amount of a compound that is an substance P receptor antagonist, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
PCT/IB1995/000811 1994-11-10 1995-09-29 Nk-1 receptor antagonists for the treatment of eye disorders WO1996014845A1 (en)

Priority Applications (3)

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MX9703483A MX9703483A (en) 1994-11-10 1995-09-29 Nk-1 receptor antagonists for the treatment of eye disorders.
EP95931373A EP0790825A1 (en) 1994-11-10 1995-09-29 Nk-1 receptor antagonists for the treatment of eye disorders
JP8515865A JPH10508837A (en) 1994-11-10 1995-09-29 NK-1 receptor antagonist for treating ocular diseases

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CA2205016A1 (en) 1996-05-23
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EP0790825A1 (en) 1997-08-27

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