WO1996014845A1 - Antagonistes du recepteur nk-1 destines au traitement de troubles oculaires - Google Patents

Antagonistes du recepteur nk-1 destines au traitement de troubles oculaires 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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alkyl
phenyl
optionally
substituted
carbon
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PCT/IB1995/000811
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English (en)
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Hans-Jurgen Ernst Hess
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Pfizer Inc.
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Priority to JP8515865A priority Critical patent/JPH10508837A/ja
Priority to EP95931373A priority patent/EP0790825A1/fr
Priority to MX9703483A priority patent/MX9703483A/es
Publication of WO1996014845A1 publication Critical patent/WO1996014845A1/fr

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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

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Abstract

La présente invention concerne un procédé de traitement ou de prévention d'un trouble oculaire dont le glaucome, l'hypertonie oculaire, la myosis, le larmoiement excessif, l'hyperémie, et la rupture de la barrière aqueuse du sang chez les mammifères, y compris chez l'homme, à l'aide d'un antagoniste du NK-1. L'invention concerne également un procédé de traitement ou de prévention de tels troubles chez les mammifères, y compris l'homme, à l'aide de certains dérivés de quinuclidine, de dérivés de pipéridine, de dérivés de pyrrolidine, de dérivés d'azanorbornane, de dérivés d'éthylène diamine et des composés correspondants qui sont des antagonistes du récepteur de la substance P.
PCT/IB1995/000811 1994-11-10 1995-09-29 Antagonistes du recepteur nk-1 destines au traitement de troubles oculaires WO1996014845A1 (fr)

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JP8515865A JPH10508837A (ja) 1994-11-10 1995-09-29 眼の疾患を治療するためのｎｋ−１レセプターアンタゴニスト
EP95931373A EP0790825A1 (fr) 1994-11-10 1995-09-29 Antagonistes du recepteur nk-1 destines au traitement de troubles oculaires
MX9703483A MX9703483A (es) 1994-11-10 1995-09-29 Antagonistas del receptor de nk-1 para el tratamiento de trastornos oculares.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014193A1 (fr) * 1996-10-04 1998-04-09 Alcon Laboratories, Inc. Utilisation d'un antagoniste de la substance p dans la fabrication d'un medicament pour traiter les douleurs oculaires

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533280A1 (fr) * 1991-09-20 1993-03-24 Glaxo Group Limited Nouvelle indication médicale pour les antagonistes des tachykinines
WO1994008997A1 (fr) * 1992-10-21 1994-04-28 Pfizer Inc. Benzylaminoquinuclidines substituees utilisees comme antagonistes de substance p
WO1994010170A1 (fr) * 1992-10-28 1994-05-11 Pfizer Inc. Quinuclidines substituees utiles comme antagonistes de la substance p
WO1994016697A1 (fr) * 1993-01-19 1994-08-04 Rhone-Poulenc Rorer S.A. Association synergisante ayant un effet antagoniste des recepteurs nk1 et nk2
EP0610021A1 (fr) * 1993-02-04 1994-08-10 Pfizer Inc. Agents pharmaceutiques dans le traitement de l'incontinence urinoire
WO1994026740A1 (fr) * 1993-05-19 1994-11-24 Pfizer Inc. Alkyle benzylaminoquinuclidines a substitution heteroatomique utilisees comme antagonistes de substances p
WO1995007908A1 (fr) * 1993-09-17 1995-03-23 Pfizer Inc. 3-benzylaminomethyl-piperidines a substitution heteroarylamino et heteroarylsulfonamido, et composes apparentes
WO1995007886A1 (fr) * 1993-09-17 1995-03-23 Pfizer Inc. Piperidines 3-amino-5-carboxy-substituees et pyrrolidines 3-amino-4-carboxy-substituees utilisees comme antagonistes de tachykinine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533280A1 (fr) * 1991-09-20 1993-03-24 Glaxo Group Limited Nouvelle indication médicale pour les antagonistes des tachykinines
WO1994008997A1 (fr) * 1992-10-21 1994-04-28 Pfizer Inc. Benzylaminoquinuclidines substituees utilisees comme antagonistes de substance p
WO1994010170A1 (fr) * 1992-10-28 1994-05-11 Pfizer Inc. Quinuclidines substituees utiles comme antagonistes de la substance p
WO1994016697A1 (fr) * 1993-01-19 1994-08-04 Rhone-Poulenc Rorer S.A. Association synergisante ayant un effet antagoniste des recepteurs nk1 et nk2
EP0610021A1 (fr) * 1993-02-04 1994-08-10 Pfizer Inc. Agents pharmaceutiques dans le traitement de l'incontinence urinoire
WO1994026740A1 (fr) * 1993-05-19 1994-11-24 Pfizer Inc. Alkyle benzylaminoquinuclidines a substitution heteroatomique utilisees comme antagonistes de substances p
WO1995007908A1 (fr) * 1993-09-17 1995-03-23 Pfizer Inc. 3-benzylaminomethyl-piperidines a substitution heteroarylamino et heteroarylsulfonamido, et composes apparentes
WO1995007886A1 (fr) * 1993-09-17 1995-03-23 Pfizer Inc. Piperidines 3-amino-5-carboxy-substituees et pyrrolidines 3-amino-4-carboxy-substituees utilisees comme antagonistes de tachykinine

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
B. PERNOW: "ROLE OF TACHYKININS IN NEUROGENIC INFLAMMATION", JOURNAL OF IMMUNOLOGY, vol. 135, no. 2, pages 812S - 815S *
G. HOLMDAHL ET AL.: "SUBSTANCE P ANTAGONIST, (D-PRO, D-TRP)SP, INHIBITS INFLAMMATORY RESPONSES IN THE RABBIT EYE", SCIENCE, vol. 214, pages 1029 - 1031 *
R. HAKANSON ET AL.: "COMPARISON OF SPANTIDE II AND CP-96,345 FOR BLOCKAGE OF TACHYKININ-EVOKED CONTRACTIONS OF SMOOTH MUSCLE", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 178, no. 1, pages 297 - 301 *
R. HAKANSON ET AL.: "TACHYKININ ANTAGONISTS SUPRESS RESPONSE TO OCULAR INJURY IN THE RABBIT", FERNSTRÖM FOUNDATION SERIES, vol. 6, pages 91 - 96 *
Z. WANG ET AL.: "CP-96,345, A SELECTIVE TACHYKININ NK1 RECEPTOR ANTAGONIST, HAS NON-SPECIFIC ACTIONS ON NEUROTRANSMISSION", BRITISH JOURNAL OF PHARMACOLOGY, vol. 107, pages 762 - 765 *
Z. WANG ET AL.: "NON-SPECIFIC ACTIONS OF THE NON-PEPTIDE TACHYKININ RECEPTOR ANTAGONISTS, CP-96,345, RP67580 AND SR 48968, ON NEUROTRANSMISSION", BRITISH JOURNAL OF PHARMACOLOGY, vol. 111, no. 1, pages 179 - 184 *
Z. WANG ET AL.: "THE ELECTRICALLY EVOKED, TACHYKININ-MEDIATED CONTRACTILE RESPONSE OF THE ISOLATED RABBIT IRIS SPHINCTER MUSCLE INVOLVES NK1 RECEPTORS ONLY", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 216, pages 327 - 329 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014193A1 (fr) * 1996-10-04 1998-04-09 Alcon Laboratories, Inc. Utilisation d'un antagoniste de la substance p dans la fabrication d'un medicament pour traiter les douleurs oculaires

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