EP0790825A1 - Antagonistes du recepteur nk-1 destines au traitement de troubles oculaires - Google Patents

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

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Publication number
EP0790825A1
EP0790825A1 EP95931373A EP95931373A EP0790825A1 EP 0790825 A1 EP0790825 A1 EP 0790825A1 EP 95931373 A EP95931373 A EP 95931373A EP 95931373 A EP95931373 A EP 95931373A EP 0790825 A1 EP0790825 A1 EP 0790825A1
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EP
European Patent Office
Prior art keywords
alkyl
phenyl
optionally
substituted
carbon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP95931373A
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German (de)
English (en)
Inventor
Hans-Jurgen Ernst Hess
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Pfizer Inc
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Pfizer Inc
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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-l 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-l 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 NRR 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 , 0, S, SO or S0 2 ;
  • Q is S0 2 , NH, -N(C,-C 6 )alkyl or (C,-C 6 )alkyl-N-S0 2 -
  • X s is the sulfur atom
  • W 1 is hydrogen, halo or (C,-C 6 ) alkyl, S-(C,-C 3 )alkyl, halo or (C,-C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • W 2 is hydrogen, (C j -C 6 )alkyl, S-(C,-C 3 )alkyl, halo or (C,-
  • W is hydrogen, (C,-C 6 )alkyl optionally substituted with from one to three fluorine atoms, -S(0) v -(C,-C 6 ) alkyl wherein v is zero, one or two, halo or (C,-C 6 )alkoxy optionally substituted with from one to three fluorine atoms;
  • X 1 is hydrogen, (C,-C 10 ) alkoxy optionally substituted with from one to three fluorine atoms or (0,-0, 0 ) alkyl optionally substituted with from one to three fluorine atoms;
  • X 2 and X 3 are independently selected from hydrogen, halo, nitro, (C,-C, 0 ) alkyl optionally substituted with from one to three fluorine atoms, (C,-C, 0 ) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C,-C 6 )-
  • 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,-C 6 )alkyl optionally substituted with from one to three fluorine atoms, (C,-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,-C 6 )alkyl optionally substituted with from one to three flu
  • 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,-C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C,-C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 1 is selected from amino, (C,-C 6 )alkylamino, di-(C,- C 6 )alkylamino, -S(O) v -(C,-C 10 )-alkyl wherein v is zero, one or two, -S(0) v -aryl wherein v is zero, one or two, -O-aryl, -S0 2 NR 4 R s wherein each of R 4 and R 5 is, independently, (C,- -7-
  • C 6 )alkyl or R 4 and R s , together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 0 0 carbons, -NHC II(C,-C 6 )alkyl, -NHCIICF 3 , (C,-C 10 )alkyl-NI-SO 2 -(C,- C, 0 )alkyl wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine
  • (C,-C 10 )alkyl-N-SO 2 -aryl 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
  • R 4 is (C,-C 6 ) alkyl or phenyl;
  • R 2 is hydrogen or -CO 2 (C,-C, 0 )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,-C, 0 ) alkyl optionally substituted with from one to three fluorine atoms, (C,-C j0 ) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C,-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 ⁇ ;
  • R 8 is hydrogen or (C,-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,-C, 0 ) alkyl optionally substituted with from one to three fluorine atoms and (C,-C, 0 ) alkoxy optionally substituted with from one to three fluorine atoms; Y 1 is (CH 2 ), 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,-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; p is zero or one; r is one, two or three;
  • R 11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C,-C, 0 ) alkyl optionally substituted with from one to three fluorine atoms and (C,-C, 0 ) 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 ),, may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) ⁇ may optionally be substituted with R 14 , and wherein any one of the carbon atoms of said (CH 2 ) 4 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,-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 a t tachment on R 12 is a carbon atom unless R 12 is hydrogen, ar vherein each of said aryl and heteroaryl groups and t ⁇ phenyl moieties of said benzyl, phenyl-(C 2
  • R 13 is hydrogen, phenyl or (C,-C 6 )alkyl; or 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 NHCR 18 , NHCH 2 R 18 , S0 2 R 18 , GR 20 C0 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,-C 6 )alkyl, hydrogen, phenyl or phenyl (C,- C 6 )alkyl;
  • G is selected from the group consisting of CH 2 , nitrogen, oxygen, sulfur and carbonyl;
  • R 20 is a monocyclic or bicycl c 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 ) distract or (CH 2 ) B+1 may be optionally substituted with (C,-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+ , 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+ , may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C 3 -C 3 ) fused carbocyclic ring; with the proviso that (a) when m is 0, one of R 16 and R 17 is absent and the other is hydrogen, (b
  • the fused bicyclic nucleus of compounds of the formula lb 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,-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,-C 3 ) alkyl moieties.
  • R 3 is a group of the formula III, VII or IX;
  • R 2 is hydrogen;
  • the fused bicyclic ring system to which W and the -CH 2 NR 2 R 3 sidechain are attached is benzoxazolyl, benzisoxazolyl, benzthiazolyl or benzimidazolyl; and
  • W is (C,-C 6 )alkoxy optionally substituted with from one to five fluorine atoms.
  • 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, 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 M 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 la or lb that is selected from: (2S,3S) -3-[2-methoxy-5-(2-thiazolyl)benzyl]amino-2- phenylpiperidine;
  • 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,-C 3 )alkoxy optionally substituted with from one to three fluorine atoms; and R 1 is
  • v is zero, one or two, -O-aryl, (C,-C, 0 )alkyl-N-SO 2 - (C,-C 10 )alkyl wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine
  • R 6 and R 7 is phenyl.
  • (13) A compound as defined in paragraph 11 above, wherein R 3 is a group of the formula VII, each of R 13 , R 14 , R ,s and R 16 is hydrogen, R 12 is phenyl, m is zero and X 4 is
  • R 13 , R 14 , R 15 and R 16 is hydrogen, is zero, X 4 is -(CH 2 ) 2 - or
  • R 1 is selected from S(O) v -(C,-C, 0 )alkyl wherein v I is zero, one or two, and (C,-C, 0 )alkyl-N-SO 2 -(C,-C, 0 )alkyl, and di-(C,-C 6 )alkylamino.
  • R ⁇ is hydrogen
  • R 12 is phenyl
  • R 14 is -C-0H
  • ring AA is phenyl
  • W 1 is (C,-C 3 ) alkoxy
  • R" is selected from (C,- C 5 ) alkyl, -SCH 3 , S0 2 CH 3 , SOCH 3 , (C,-C 6 ) alkylamino and di-(C,- C 6 ) alky 1 -amino .
  • a compound of the formula Ic having the formula (36) A compound of the formula Id wherein R 6 , R 10 , R 11 and R 13 are phenyl, R 8 is hydrogen, R 9 is phenyl optionally substituted with chlorine, fluorine, (Cj-C 6 ) alkyl optionally substituted with from one to three fluorine atoms or (C,-C 6 ) alkoxy optionally substituted with from one to three fluorine atoms, is 0 and n is 3 or 4.
  • 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,-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 ) B ;
  • Y is optionally substituted (C,-C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl or optionally substituted (C 3 - C 8 )cycloalkyl;
  • X is optionally substituted (C,-C 6 )alkoxy, hydroxy, CONR'R 2 , COjR 1 , CHR'OR 2 , CHR'NR ⁇ 3 , COR 1 , CONR'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.
  • R 1 , R 2 and R 3 are independentl selected from hydrogen, optionally substituted (C,-C 6 )alkyl, optionally substituted (C,-C 6 )alkoxy, optionally substituted (C 3 - C g )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 (C,-C 5 )heterocyclic groi; s, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl
  • 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,-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, nitro
  • 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
  • R 5 and R 6 is hydrogen and the other is selected from hydroxymethyl, hydrogen, (C,-C 3 )alkyl, (C,-C 8 )acyloxy- (C,-C 3 )alkyl, (C,-C 8 )alkoxymethyl and benzyloxymethyl;
  • R 7 and R 8 are independently selected from hydrogen, (C,- C 3 )alkyl and phenyl;
  • R 9 is selected from methyl, hydroxymethyl, O
  • R 14 R s NC0 2 CH 2 -, R ,6 OC0 2 CH 2 -, (C,-C 4 )alkyl-C0 2 CH 2 -, -CONR ,7 R 18 , R ,7 R 18 NC0 2 -, R 19 OC0 2 -, C 6 H 5 CH 2 C0 2 CH 2 -, C 6 H 5 C0 2 CH 2 -, (C,-C 4 )alkyl- CH(OH)-, C 6 H 5 CH(OH)-, C 6 H s CH 2 CH(OH)-, CH 2 halo, R 0 SO 2 OCH 2 , -C0 2 R 16 and R 21 C0 2 -;
  • R 10 and R n are independently selected from hydrogen, (C,- C 3 ) alkyl and phenyl;
  • R 12 is hydrogen, benzyl or a group of the formula
  • R 23 I (CH 2 ) .
  • 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,-C 3 )alkyl and phenyl;
  • R 22 and R 23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C,-C 6 )alkyl, (C,- C 6 )alkylamino, di-(C,-C 6 )alkylamino, (C,-C 6 )alkoxy, (C,-C 6 )- 0 0 0 0 0
  • Preferred embodii. s 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.
  • 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 diphenylmethy1
  • 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, -C0 2 R 16 , -CONR ,7 R 18 , R 1 R 1S NC0 2 CH 2 -, R 16 OC0 2 CH 2 -, (C,-C 4 )alkyl-C0 2 CH 2 -, C 6 H s CH 2 C0 2 CH 2 -, -CH 2 halo and R 20 SO 2 OCH 2 -
  • R 12 is hydrogen or benzyl.
  • (2SR, 3SR, 4RS) -2 -dipheny lmethy 1-3 -[ (2-methoxy-5- trif luoromethoxyphenyl) 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
  • R 1 is hydrogen, (C,-C 8 ) alkyl, a saturated (C 6 -C, 0 ) c a rbocyclic ring system containing two fused rings, a urated (C 6 -C, 0 ) carbocyclic bridged ring system containing j rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C,-C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C,-C 8 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 2 is hydrogen, benzyl or a group of the formula
  • R 8 and R 9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C,-C 6 )alkyl, (C,-C 6 )alkylamino, di-(C,-C 6 )alkylamino, (C,-C 6 )alkoxy, 0 0
  • benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; or 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 ators, a fused bicyclic ring containing from six to ten carbon ato ⁇ , or a saturated bridged ring system containing fror 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,-C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C,-C 6 ) alkoxy optionally substituted with from one to
  • R 3 is hydrogen, (C 3 -C 8 )cycloalkyl, (C,-C 6 ) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C,- C 6 )alkyl optionally substituted with from one to three fluorine atoms, and (C,-C 6 )alkoxy optionally substituted with from one to three fluorine atoms;
  • R s is hydrogen, (C,-C 6 )alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C,-C 6 )alkyl optionally substituted with from one to three fluorine atoms and (C,-C 6 )alkoxy optionally substituted with from one to three fluorine atoms;
  • R 6 is selected from hydrogen, (C,-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 ( ⁇ -Cg) 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, nitro, (C
  • R 12 is hydrogen, (C,-C 3 )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.
  • 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;
  • R 4 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,-C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C,-C 6 ) alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C,-C 6 ) alkylamino, -C(0)NH-(C,-C 8 )alkyl, (C,-C 6 )alkyl-C(0)-, -C(0)-0-(C,-C 6 )alkyl, -C(0)H, -CH
  • 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)
  • each of R 2 , R 3 and R 5 is hydrogen.
  • a compound of the formula XII that is selected from the group consisting of: l-N-cyclohexyl-l-phenyl-2-N , -[ (2-methoxyphenyl)methyl]- 1,2-ethanediamine; l-N-cyclohexyl-l-phenyl-2-N' - [ ( 2-methoxy-5- trifluoromethoxyphenyl)methyl]-1,2-ethanediamine; l-N-pyrrolidyl-l-phenyl-2-N , -[ (2-methoxyphenyl)methyl]- 1,2-ethanediamine; l-N-methyl-l-phenyl-2-N , -[ (2-methoxyphenyl)methyl]-1,2- ethanediamine; l-N-cyclopentyl-l-phenyl-2-N'-[ (2-methoxyphenyl) methyl]-1,2-ethanediamine; l-N-propyl-l-pheny
  • 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 atom
  • 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 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,-C 8 ) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
  • R 2 is a group selected from hydrogen, (C,-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 benzy
  • R s is hydrogen, phenyl or (C,-C 6 )alkyl; or 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, ⁇ ndan l, 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,-C 6 )alkyl optionally substituted with from one to three fluorine atoms, (C,-C 6 )alkoxy optionally substituted with from one to three fluor
  • R 6 is NHC IIR , 9 , NHCH 2 R 9 , NHS0 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,-C 6 )alkyl, hydrogen, phenyl or phenyl (C,- C 6 )alkyl; with the proviso that (a) when m is 0, R 8 is absent and R 6 is hydrogen, (b) neither R 4 , R 6 , nor R 8 can form, together with the carbon to which it is attached, a ring with R 5 , (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.
  • 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,-C 6 ) alkyl, (C,-C 6 )alkoxy, trifluoromethyl, amino,
  • 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,-C 6 ) alkyl, (C,-C 6 ) alkoxy, trifluoromethyl, amino,
  • 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,-C 5 alkoxy or halosubstituted (C,-C 3 ) alkoxy;
  • X 2 is hydrogen, halogen, (C,-C 5 )alkyl, (C 2 -C 3 )alkenyl, (C 2 -C 5 )alkynyl, (C,-C 5 )alkoxy, (C,-C 5 )alkylthio, (C,-C 5 ) alkylsulfinyl, (C,-C 5 ) alkylsulfonyl, halosubstituted (C,-C 5 ) alkyl, halosubstituted (C,-Cs) alkoxy, (0,-0,)alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C,-C 5 )alkylsulfonylamino (which may be substituted
  • Ar 1 and Ar 2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
  • A is Y-(CH 2 ) m -CH(R)-(CH 2 ) n -NR 1 -;
  • R 1 is hydrogen, (C,-C j )alkyl, benzyl or -(CH 2 ) p -Y;
  • R 2 is hydrogen, (C,-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- indolylmethy1 or -(CH 2 ) p -Y;
  • Y is -CN, -CH 2 Z or -COZ;
  • Z is hydroxy, amin?, (C,-C 5 )alkoxy, (C,-c 5 ) alkylamino or dialkylamino having frc ⁇ 1 to 5 carbon atoms in each alkyl moiety;
  • m, n and p are each, independently, 0, 1, 2 or 3; and R 1 and R 2 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.
  • 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,-C, 0 ) alkyl optionally substituted with from one to three fluorine atoms, (C,-C, 0 ) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C,-C 6 )-alkylamino,
  • said -S(0) v -aryl, -0-aryl and (C,-C, 0 )alkyl-N I-S0 2 -aryl are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C,-C 4 )alkyl, (C,- C 4 )alkoxy and halo; or 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,-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 substituents
  • R 3 is selected from NHCR 8 , NHCH 2 R 8 , S0 2 R 8 , AR 9 , C0 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,-C 6 )alkyl, hydrogen, phenyl or phenyl (C,- 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 ) 0+ , may be optionally substituted with (C,-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+l may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH 2 ) classroom and (CH 2 ) n+J may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C 3 -C 3 ) 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 ;
  • R 6 or R 7 when m is zero, one of R 3 and R 4 is absent and the other is hydrogen; and (c) when R 6 or R 7 is attached to a carbon atom of X that is adjacent to the ring nitrogen, then R 6 or R 7 , 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.
  • 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.
  • a compound as defined in paragraph (70)-(75) below or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing
  • R 1 is phenyl substituted with from one to three substituents independently selected from (C,-C 6 )alkyl optionally substituted with from one to three fluorine atoms and (C,- C 6 )alkoxy optionally substituted with from one to three flourine atoms.
  • 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 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; 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.
  • 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(0) (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 , -C0 2 R 3 , -CH 2 OR 3 , -CH 2 NR 3 R 4 or -CONR 3 OR 4 ;
  • R 1 , P. 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-alkyl- N-alkanoylamino (which may be substituted by halogen in the alkanoyl moiety) having l 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 l to 4 carbon
  • 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- methylsulf onylamino .
  • 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 is C,-C 6 alkyl having one or more substituents bonded through a heteroato ;
  • Ar 1 and Ar 2 are each, independently, aryl optionally substituted by one C,-C 6 alkyl, C,-C 6 alkoxy, C,-C 6 alkylthio, halogen, cyano, nitro, phenoxy, mono C,-C 6 alkylamino, di C,- C 6 alkylamino, halosubstituted C.-C 6 alkyl, or halosubstituted C,-C 6 alkoxy;
  • Y is hydrogen, C.-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 ) D -NR'co- wherein Y is at the 4-, 5- or 6-position on the quinuclidine ring;
  • R 1 is hydrogen, C,-C 6 alkyl, benzyl or -(CH 2 ) r -W;
  • R 2 is hydrogen or C,-C 6 alkyl which may be substituted by one hydroxy, amino, methylthio, mercapto, benzyl, 4- hydroxybenzyl, 3-indolylmethy1 or -(CH 2 ) r -W;
  • Z is C,-C 6 alkoxy, -CONR 4 R 5 , -C0 2 R 4 , -CHR 4 0R 5 , -CHR 4 NR 5 R 6 , -COR 4 , -CONR 4 OR s or optionally substituted aryl; each W is independently cyano, hydroxymethyl, C 2 -C 6 alkoxymethyl, aminomethyl, mono C,-C 6 alk, laminomethyl, di C,- alkylaminomethyl, carboxyl, carbamoyl or c,-c 6 alkoxycarbonyl;
  • R 4 , R 5 and R 6 are independently hydrogen, C,-C 6 alkyl, C,- C 6 alkoxy, C 3 -C 8 cycloalkyl or an optionally substituted aryl or heterocyclic grour;; p is 0 to 6; and , 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.
  • 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,-C 6 alkyl, halosubstituted C,-c 6 alkyl, Cj-C 6 alkoxy, C,-C 6 alkylthio, C,- C 6 alkylsulfinyl, C,-C 6 alkylsulfonyl or tri C,-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,-C 6 alkoxy, NR 3 wherein
  • R 1 and R 2 when taken separately, are each hydrogen or C,-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,-C 6 alkyl, benzyl or -(CH 2 ) r -W 2 ;
  • R 4 is hydrogen or C,-C 6 alkyl which may be substituted by hydroxy, amino, methylthio, mercapto, benzyl, 4- hydroxylbenzyl, 3-indolylmethy1 or -(CH 2 ),-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,-C 6 alkylamino)methyl, (di C,-C 6 alkylamino)methyl, carboxyl, (C,-C 6 alkyl)carbamoyl, or (di
  • alkylthio means -S- alkyl, including but not limited to ethylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like;
  • alkylsulfonyl means
  • aryl means aromatic radicals including but not limited to phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl and the like.
  • aryl groups can be substituted by C,-C 6 alkyl, C,-C 6 alkoxy, C,-C 6 alkylthio, halogen, cyano, nitro, phenoxy, mono- or di-C,-C ⁇ 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.
  • a compound as defined in paragraph (92) below, or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such disorder.
  • (3S,4R,5S,6S) -6-diphenylmethy1-5- (3-fluoro-5- trifluoromethylbenzyloxy) -l-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
  • 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 1 is phenyl, biphenyl, indanyl, naphthyl, thienyl, furyl, pyridyl, thiazolyl, isothiazoiyl, oxazolyl, isoxazolyl, tetrazolyl, quinolyl, phenyl C,-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,-C 6 alkyl, halosubstituted C,-C 6 alkyl, C,-C 6 alkoxy and halosubstituted C,-C 6 alkoxy;
  • R 2 is hydrogen or C,-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,-C 6 alkyl, halosubstituted C,-C ⁇ alkoxy, halosubstituted C,-C 6 alkoxy, hydroxy, amino, C,-C 6 alkylthio, C,-C 6 alkylsulfinyl or C,-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,-C 6 alkyl;
  • R 6 is hydrogen, halogen, C,-C 6 alkyl, halosubstituted C,- C 6 alkyl or C,-C 6 alkoxy; provided that when Z is a valence bond, R 3 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.
  • 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, l- and 2-propenyl, 2-methyl-l-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.
  • 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 la, lb, 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 la, lb, 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 la, lb, 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 la, lb, 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 la, lb, 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 la, lb, 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-l 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-l 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-l 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-l 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 S0 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-l,3-propanediol) hydrochloride buffer having a pH of 7.7.
  • Tris i.e., trimethamine which is 2-amino-2-hydroxymethyl-l,3-propanediol
  • the homogenate is centrifuged at 30,000 x G for a period of 20 minutes.
  • the pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 x 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 100 ⁇ l of radioactive ligand made up to a final concentration 0.5 mM and then finally by the addition of 800 ⁇ l 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 ( ⁇ a . 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 IC 50 values are calculated by using standard statistical methods.
  • 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 IC 50 values are calculated by using standard statistical methods.

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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.
EP95931373A 1994-11-10 1995-09-29 Antagonistes du recepteur nk-1 destines au traitement de troubles oculaires Withdrawn EP0790825A1 (fr)

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US336955 1994-11-10
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AU2462097A (en) * 1996-10-04 1998-04-24 Alcon Laboratories, Inc. The use of a substance p antagonist for the manufacture of medicament for the treatment of ocular pain

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DK0533280T4 (da) * 1991-09-20 2005-02-28 Glaxo Group Ltd Ny medicinsk anvendelse af tachykininantagonister
JP2656699B2 (ja) * 1992-10-21 1997-09-24 ファイザー製薬株式会社 置換ベンジルアミノキヌクリジン
JP2656700B2 (ja) * 1992-10-28 1997-09-24 ファイザー製薬株式会社 置換キヌクリジン誘導体
FR2700472B1 (fr) * 1993-01-19 1995-02-17 Rhone Poulenc Rorer Sa Association synergisante ayant un effet antagoniste des récepteurs NK1 et NK2.
US5340826A (en) * 1993-02-04 1994-08-23 Pfizer Inc. Pharmaceutical agents for treatment of urinary incontinence
IL109646A0 (en) * 1993-05-19 1994-08-26 Pfizer Heteroatom substituted alkyl benzylamino-quinuclidines
PT719253E (pt) * 1993-09-17 2004-07-30 Pfizer Piperidinas 3-amino-5-carboxi-substituidas e pirrolidinas 3-amino-4-carboxi-substituidas como antagonistas de taquicinina
US5703065A (en) * 1993-09-17 1997-12-30 Pfizer Inc. Heteroarylamino and heteroarylsulfonamido substituted 3-benyzlaminomethyl piperidines and related compounds

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