WO1996024582A1 - 5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist - Google Patents
5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist Download PDFInfo
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- WO1996024582A1 WO1996024582A1 PCT/GB1996/000259 GB9600259W WO9624582A1 WO 1996024582 A1 WO1996024582 A1 WO 1996024582A1 GB 9600259 W GB9600259 W GB 9600259W WO 9624582 A1 WO9624582 A1 WO 9624582A1
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- 0 *c1c(CC(C2(CC3)CC*3N)=O)c2c(*)c(*)c1*=C Chemical compound *c1c(CC(C2(CC3)CC*3N)=O)c2c(*)c(*)c1*=C 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Definitions
- This invention concerns novel substituted 5-(heterocyclic)valeryl derivatives which antagonize the pharmacological actions of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin 1 (NK1) and the neurokinin 2 (NK2) receptors.
- the novel 5-(heterocyclic)valeryl derivatives are useful whenever such
- Such compounds may be of value in the treatment of those diseases in which the NK1 and/or NK2 receptor is implicated, for example, in the treatment of asthma and related conditions.
- the invention also provides pharmaceutical compositions containing the novel 5-(heterocyclic)valeryl derivatives for use in such treatment, methods for their use. and processes and intermediates for the manufacture of the novel
- the mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems.
- the three principal neurokinins are SP (SP), Neurokinin A (NKA) and Neurokinin B (NKB). There are also N-terminally extended forms of at least NKA.
- At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, the receptors are classifed as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors, respectively.
- NK1 neurokinin 1
- NK2 neurokinin 2
- NK3 neurokinin 3
- C-afferent sensory neurons which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers.
- C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics.
- the effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation, increased mucus secretion and activation of mast cells.
- tachykinins are implicated in the pathophysiology and airway hyperresponsiveness observed in asthmatics; and blockade of the action of released tachykinins may be useful in the treatment of asthma and related conditions.
- a cyclopeptide antagonists (FK-224) selective for both NK1 and NK2 receptors has demonstrated clinical efficacy in human patients suffering from asthma and chronic bronchitis. M. Ichinose, et al., Lancet. 1992, 340, 1248.
- Nonpeptidic tachykinin antagonists have been reported, for example in European Patent Application. Publication Number (EPA) 428434. EPA 474561, EPA 512901, EPA 512902.
- Q 1 is a radical selected from the group of radicals of formulae la, lb, Ic, Id, le, If, Ig, Ih, Ij , Ik , Im, In, Ip, Iq, Ir, Iu, Iv, Iw and Ix wherein for a radical of formula la, Z a is nitrogen or a group CR ad in which R ad is hydrogen or R ad together with R ac and the existing carbon to carbon bond forms a double bond; R 33 is Ar or Het; R ab is hydrogen and R ac is hydrogen or hydroxy or R ac together with R ad and the existing carbon to carbon bond forms a double bond, or R ac and R ad together form a diradical -(CH 2 ) j - in which j is an integer from 1 to 5; or R ab and R ac together form a diradical -(CH 2 ) k - in which k is an integer from 2 to 6. or R ab and R
- R ae and R af are independently hydrogen or (1-4C)alkyl, or the radical NR ae R af is pyrrolidino, piperidino or morpholino;
- R bb (CH 2 ) p -C-R bc in which R bb is Ar or Het; p is the integer 0 or 1; and R bc is hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR bd (wherein R bd is hydrogen or
- R bf is independently hydrogen, (1-4C)alkyl, (1-4C)hydroxyalkyl or (1-4C)alkanoyl, or the radical NR be R bf is pyrrolidino, piperidino or morpholino; and R bg is hydrogen or
- R bc forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the piperidine ring; or Z b is a disubstituted methylene group R bh CR bi which forms a spirocyclic ring wherein R bh is phenyl which is joined by an
- ortho-substituent diradical X b to R bi in which the phenyl R bh may bear a further substituent selected from halo, (1-3C)alkyl, (1-3C)alkoxy, hydroxy, (1-3C)alkylthio, (1-3C)alkylsulfinyl and (1-3C)alkylsulfonyl; the diradical X b is methylene.
- R bi is oxy or imino of formula -NR bj - in which R bj is hydrogen or (1-3C)alkyl; for a radical of formula Ic, R ca is Ar or Het; and Z c is oxo, thio, sulfinyl, sulfonyl or imino of formula -NR cb - in which R cb is (1-3C)alkyl or R cc R cd N-(CH 2 ) q - in which q is the integer 2 or 3 and in which R cc and Rc d are independently hydrogen or (1-3C)alkyl or the radical R cc R cd N is pyrrolidino, piperidino or morpholino; for a radical of formula Id, R da is 1, 2 or 3;
- J e is oxygen, sulfur or NR ea in which R ea is hydrogen or (1-3C)alkyl;
- R eb is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)alkenyl (in which a vinyl carbon is not bound to nitrogen), 2-hydroxyethyl, (3-7C)cyloalkyl, Ar or Het;
- R ec is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)cycloalkyl, (1-5C)alkoxy (only when J e is oxygen), (3-6C)cycloalkoxy (only when J e is oxygen), or an amino group of formula NR ed R ee containing zero to seven carbon atoms in which each of R ed and R ee is independently hydrogen, (1-5C)alkyl or (3-6C)cyclo
- J f is oxygen, sulfur or NR fa in which R fa is hydrogen or (1-3C)alkyl
- L f is a divalent hydrocarbon group in which the 1 -position is bound to the carbon bearing the group J f , the divalent group L f being selected from trimethylene, cis-propenylene, tetramethylene, cis-butenylene, cis-but-3-enylene, cis,cis-butadienylene, pentamethylene and cis-pentenylene which divalent group L f itself may bear one or two methyl substituents;
- Z g is (1-8C)alkyl or (3-8C)cycloalkyl which may bear one or more substituents selected from the group consisting of halo, (3-6C)cycloalkyl. cyano, nitro. hydroxy, (1-4C)alkoxy, (1-5C)alkanoyloxy, aroyl. heteroaroyl, oxo, imino (which may bear a (1-6C)alkyl, (3-6C)cycloalkyl, (1-5C)alkanoyl or aroyl substituent).
- R ge is hydrogen or (1-4C)alkyl and R gf together with R gg forms an ethylene or trimethylene group
- R gg is hydrogen, (1-4C)alkyl or together with R gf forms an ethylene or trimethylene group
- R gj is cyano, nitro or SO 2 R gk and R gk is (1-4C)alkyl or phenyl
- R gh and R gi are independently (1-3C)alkyl; and in which a cyclic group which is a substituent on Z g or formed by substitution on Z g may bear one or more (1-3C)alkyl groups on carbon as further substituents; and in which any aryl or heteroaryl group which is a part of the group Z g may bear one or more halo, (1-4C)aIkyl
- M n denotes a heteroatom, a substituted heteroatom, or a single bond
- L h denotes a hydrocarbon radical in which the 1 -position is attached to M h ; wherein the values of G h , J h , M h and L h are selected from
- G h is a single bond; J h is oxo or thioxo; M h is oxy, thio or NR ha ; and L h is
- G h is a single bond; J h is NR hb ; M h is NR ha ; and L h is L ha ;
- G h is a double bond
- J h is OR ha , SR ha or NR hc R hd
- M h is nitrogen: and L h is
- G h is methylene which may bear one or two methyl substituents; J h is oxo. thioxo or NR he : M h is oxy. thio. sulf ⁇ nyl. sulfonyl or NR ha ; and L h is L hb ;
- G h is a single bond; J h is oxo. thioxo or NR he ; M h is nitrogen; and L h is L hc ;
- G h is methine. which may bear a (1-3C)alkyl substituent; J h is oxo, thioxo or NR he ; M h is nitrogen; and L h is L hd ;
- G h is cis-vinylene, which may bear one or two methyl substituents; J h is oxo. thioxo, or NR he ; M h is nitrogen; and L h is L he ; and
- G h is a single bond; J h is oxo or thioxo; M h is a single bond; and L h is L hf ;
- R ha is hydrogen or (1-3C)alkyl
- R hb is hydrogen, (1-3C)alkyl, cyano, (1-3C)alkylsulfonyl or nitro
- R hc and R hd are independently hydrogen or (1-3C)alkyl or the radical NR hc R hd is pyrrolidino.
- piperazinyl which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position
- R he is hydrogen or (1-3C)alkyl
- L ha is ethylene, cis-vinylene, trimethylene or tetramethylene which radical L ha itself may bear one or two methyl substituents
- L hb is ethylene or trimethylene which radical L hb itself may bear one or two methyl substituents
- L hc is
- B j is a direct bond and L j is a hydrocarbon chain in which the 1 -position is bound to B j and L j is selected from trimethylene. tetramethylene, cis-1-butenylene and cis.cis-butadienylene; or Bi is N(R jh ) and L j is a hydrocarbon chain selected from ethylene, trimethylene and cis-vinylene; or B j is N and L j is a hydrocarbon chain in which the
- R jd and R je are independently (1-3C)alkyl or together form a divalent hydrocarbon chain selected from ethylene and trimethylene;
- G k is a direct bond.
- G k is a radical having the formula -CH 2 -
- J k is oxygen or sulfur;
- Z k is -OR ka .
- -SR ka , -COR ka , -COOR ka , -C( J ka )NR kb R k c or
- R ka is oxygen or sulfur:
- R ka and R kf are independently hydrogen or (1-6C)alkyl;
- R kb and R kc are independently hydrogen or (1-6C)alkyl; or the radical NR kb R kc is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position);
- R kd and R ke are
- Z k is an imido radical selected from phthalimido. succinimido. maleimido, glutarimido, and 3-oxa-, 3-thia- and 3-azaglutarimido. in which the imido radical may bear one or more (1-3C)alkyl substituents and.
- the aromatic portion of the phthalimido may bear one or more halo, hydroxy or (1-3C)alkoxy substituents; for a radical of formula Im, R ma and R mb are Ar or Het and R mc is selected from hydroxy, (1-3C)alkoxy, and (1-3C)acyloxy; or R ma is (Ar)oxy, or (Het)oxy, and R mb and Rmc are hydrogen; for a radical of formula In, X n is selected from hydrogen, hydroxy, (1-3C)alkoxy and (1-3C)acyloxy; for a radical of formula Ip, R pa and R pb are independently selected from hydrogen, hydroxy, (1-3C)alkoxy, (1-3C)acyloxy, halo, cyano, and trifluoromethyl; for a radical of formula Iq, R qa -R qd are are independently selected from hydrogen, hydroxy, (1-3C)alkoxy, (1-3C)acyloxy, halo,
- Ju is oxygen or sulfur: and R ua -R ud are independently selected from hydrogen, (1-4C)alkyl, (1-4C)hydroxyalkyl and (1-4C)alkanoyl. or the group NR ua R ub or the group NR uc R ud is pyrrolidino, piperidino or morpholino;
- w is 1 , 2, or 3; and wherein for a radical Q 1 , Ar is a phenyl radical or an ortho-fused bicyclic carbocyclic radical of nine of ten ring atoms in which at least one ring is aromatic, which radical Ar may be unsubstituted or may bear one or more substituents selected from halo, cyano,
- n is the integer 0, 1, or 2;
- R xa is (1-6C)alkyl,
- (3-6C)cycloalkyl or phenyl which phenyl may bear a halo, trifluoromethyl, (1-3C)alkyl or (1-3C)alkoxy substitutent);
- Het is a radical (or stable N-oxide thereof) attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an ortho-fused bicyclic heterocycle derived therefrom by fusing a propenylene, trimethylene, tetramethylene or benz-diradical, which radical Het may be unsubstituted or may be substituted on carbon by one or more of the substituents defined above for Ar and may be substituted on nitrogen by (1-3C)alkyl;
- Q 2 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q 2 is thienyl. imidazolyl. benzo[b]thiophenyl or naphthyl any of which may bear a halo
- Q 2 is biphenylyl: or Q 2 is carbon-linked indolyl which may bear a benzyl substituent at the 1-position;
- Q 3 is hydrogen, or (1-4C)alkyl:
- Q 4 is -OR 2 or -NR 3 R 4 : wherein
- R 3 and R 4 are independently selected from hydrogen. (1-8C)alkyl, norbornyl, adamantyl, quinuclidinyl, (1-6C)alkoxy, (3-7C)cycloalkyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, 1 -benzylpiperidyl, 4,5-dihydrothiazolyl, 3,4,5,6-tetrahydrophenyl, fluorenyl, 5-oxo-4,5-dihydropyrazol-3-yl, aryl, heteroaryl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, 1-phenyl-4,5-dihydropyrazol-3-yl, 1-benzylpyrrolidin-3-yl, and a radical of formula VII; wherein (1-8C)alkyl may be substituted by one.
- phenyl or phenyl portion of benzyl may optionally bear one, two or three substituents independently selected from halo,
- n 1 or 2;
- R 5 -R 1 1 are independently selected from hydrogen and (1-3C)alkyl or the N-oxide of the nitrogen in Q 1 indicated by ⁇ in formulae Ia-Ix (or of either basic piperazinyl nitrogen of Q 1 when Z a is nitrogen);
- (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.
- a particular sub-set of compounds of the invention are compounds of formula I wherein: Q 1 is a radical selected from the group of radicals of formulae la, lb, Ic, Id, Ie, If, Ig. Ih, Ij and Ik wherein for a radical of formula la.
- Z a is nitrogen or a group CR ad in which R ad is hydrogen or R ad together with R ac and the existing carbon to carbon bond forms a double bond:
- R 33 is Ar or Het;
- R ab is hydrogen and R ac is hydrogen or hydroxy or R ac together with R ad and the existing carbon to carbon bond forms a double bond, or
- R ac and R ad together form a diradical -(CH 2 ) j - in which j is an integer from 1 to 5; or
- R ab and R ac together form a diradical -(CH 2 ) k - in which k is an integer from 2 to 6, or
- R ae and R af are independently hydrogen or (1-4C)alkyl. or the radical NR ae R af is pyrrolidino, piperidino or morpholino; for a radical of formula Ib, Z b is a substituted imino group R ba N or R ba CH 2 N in which R ba is (3-7C)cycloakyl, Ar or Het; or Z b is a disubstituted methylene group
- R bb (CH 2 ) p -C-R bc in which R bb is Ar or Het; p is the integer 0 or 1; and R bc is hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR bd (wherein R bd is hydrogen or
- R be and R bf are independently hydrogen, (1-4C)alkyl, (1-4C)hydroxyalkyl or (1-4C)alkanoyl, or the radical NR bc R bf is pyrrolidino, piperidino or morpholino; and R bg is hydrogen or (1-4C)alkyl; or R bc forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the piperidine ring; or Z b is a disubstituted methylene group R bh CR bi which forms a spirocyclic ring wherein R bh is phenyl which is joined by an ortho-substituent diradical X b to R bi in which the phenyl R bh may bear a further substituent selected from halo, (1-3C)alkyl, (1-3C)alk
- R cb is (1-3C)alkyl or R cc R cd N-(CH 2 ) q - in which q is the integer 2 or 3 and in which R cc and R cd are independently hydrogen or (1-3C)alkyl or the radical R cc R cd N is pyrrolidino, piperidino or morpholino; for a radical of formula Id, R da is 1, 2 or 3;
- J e is oxygen, sulfur or NR ea in which R ea is hydrogen or (1-3C)alkyl; R eb is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)alkenyl (in which a vinyl carbon is not bound to nitrogen). 2-hydroxyethyl, (3-7C)cyloalkyl.
- R ec is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)cycloalkyl, (1-5C)alkoxy (only when J e is oxygen), (3-6C)cycloalkoxy (only when J e is oxygen), or an amino group of formula NR ed R ee containing zero to seven carbon atoms in which each of R ed and R ee is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NR ed R ee is pyrrolidino, piperidino. morpholino. thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl group may bear a (1-3C)alkyl substituent at the 4-position);
- J f is oxygen, sulfur or NR fa in which R fa is hydrogen or (1-3C)alkyl
- L f is a divalent hydrocarbon group in which the 1 -position is bound to the carbon bearing the group J f , the divalent group L f being selected from trimethylene, cis-propenylene, tetramethylene, cis-butenylene, cis-but-3-enylene. cis,cis-butadienylene, pentamethylene and cis-pentenylene which divalent group L f itself may bear one or two methyl substituents;
- R gf is pyrrolidino, piperidino. morpholino. thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position) or R ge is hydrogen or (1-4C)alkyl and R gf together with R gg forms an ethylene or trimethylene group; R gg is hydrogen. (1-4C)alkyl or together with R gf forms an ethylene or trimethylene group; R gj is cyano.
- R gk and R gk is (1-4C)alkyl or phenyl;
- R gh and R gi are independently (1-3C)alkyl; and in which a cyclic group which is a substituent on Z g or formed by substitution on Z g may bear one or more (1 -3C)alkyl groups on carbon as further substituents; and in which any aryl or heteroaryl group which is a part of the group Z g may bear one or more halo, (1-4C)alkyl, (1-4C)alkoxy. cyano.
- G h denotes a single bond, a double bond or a divalent hydrocarbon radical
- J h denotes a radical joined to the ring by a single bond if G h denotes a double bond or. otherwise, a radical joined by a double bond
- M h denotes a heteroatom, a substituted heteroatom, or a single bond
- L h denotes a hydrocarbon radical in which the 1-position is attached to M h ; wherein the values of G h , J h , M h and L h are selected from
- G h is a single bond; J h is oxo or thioxo; M h is oxy, thio or NR ha ; and L h is
- G h is a single bond; J h is NR hb ; M h is NR ha ; and L h is L ha ;
- G h is a double bond
- J h is OR ha , SR ha or NR hc R hd
- M h is nitrogen
- L h is
- G h is methylene which may bear one or two methyl substituents; J h is oxo, thioxo or NR he ; M h is oxy, thio, sulfinyl, sulfonyl or NR ha ; and L h is L hb ; (e) G h is a single bond; J h is oxo. thioxo or NR he ; M h is nitrogen; and L h is L hc ;
- G h is methine. which may bear a (1-3C)alkyl substituent: J h is oxo, thioxo or NR he : M h is nitrogen: and L h is L hd ;
- G h is cis-vinylene, which may bear one or two methyl substituents; J h is oxo. thioxo, or NR he ; M h is nitrogen; and L h is L he ; and
- G h is a single bond; J h is oxo or thioxo; M h is a single bond: and L h is L hf ;
- R ha is hydrogen or (1-3C)alkyl
- R hb is hydrogen, (1-3C)alkyl.
- R hc and R hd are independently hydrogen or (1-3C)alkyl or the radical NR hc R hd is pyrrolidino, piperidino.
- L ha is ethylene, cis-vinylene, trimethylene or tetramethylene which radical L ha itself may bear one or two methyl substituents
- L hb is ethylene or trimethylene which radical L hb itself may bear one or two methyl substituents
- L hc is
- B j is a direct bond and L j is a hydrocarbon chain in which the 1 -position is bound to B j and L j is selected from trimethylene, tetramethylene, cis-1-butenylene and cis,cis-butadienylene; or B j is N(R jh ) and L j is a hydrocarbon chain selected from ethylene, trimethylene and cis-vinylene; or B j is N and L j is a hydrocarbon chain in which the
- G k is a direct bond
- G k is a direct bond
- G k is a radical having the formula -CH 2 -
- J k is oxygen or sulfur;
- J ka is oxygen or sulfur
- R ka and R kf are independently hydrogen or (1-6C)alkyl
- R kb and R kc are independently hydrogen or (1-6C)alkyl
- the radical NR kb R kc is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position)
- R kd and R ke are
- Z k is an imido radical selected from phthalimido. succinimido. maleimido, glutarimido, and 3-oxa-, 3-thia- and 3-azaglutarimido, in which the imido radical may bear one or more (1-3C)alkyl substituents and.
- the aromatic portion of the phthalimido may bear one or more halo, hydroxy or (1-3C)alkoxy substituents: and wherein for a radical Q 1 , Ar is a phenyl radical or an ortho-fused bicyclic carbocyclic radical of nine often ring atoms in which at least one ring is aromatic, which radical Ar may be unsubstituted or may bear one or more substituents selected from halo, cyano,
- n is the integer 0, 1, or 2;
- R xa is (1-6C)alkyl,
- (3-6C)cycloalkyl or phenyl which phenyl may bear a halo, trifluoromethyl, (1-3C)alkyl or (1 -3C)alkoxy substituted
- the radical NR xb R xc contains zero to seven carbons and each of Rx b and R xc is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NR xb R xc is pyrrolidino, piperidino. morpholino, thiomorpholine (or its S-oxide) or.
- R xj is hydrogen, (1-5C)alkylsulfonyl or phenylsulfonyl; and R xj is hydrogen, (1-5C)alkyl or benzyl; and Het is a radical (or stable N-oxide thereof) attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an ortho-fused bicyclic heterocycle derived therefrom by fusing a propenylene, trimethylene, tetramethylene or benz-diradical, which radical Het may be unsubstituted or may be substituted on carbon by one or more of the substituents defined above for Ar and may be substituted on nitrogen by (1-3C)alkyl; Q 2 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and
- Q 3 is hydrogen, or (1-4C)alkyl:
- Q 4 is -OR 2 or -NR 3 R 4 ;
- R 2 is hydrogen. (1-6C)alkyl, (3-7C)cycloalkyl. aryl(1-3C)alkyl or heteroaryl(1-3C)alkyl, wherein an aryl or heteroaryl group may bear one, two or three substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl. cyano.
- -NR 3 R 4 taken together represents a cyclic amino radical selected from pyrrolidinyl, piperidino, 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydroquinolyl, and
- R 5 -R 1 1 are independently selected from hydrogen and (1-3C)alkyl or the N-oxide of the nitrogen in Q 1 indicated by ⁇ in formulae la-Ik (or of either basic piperazinyl nitrogen of Q 1 when Z a is nitrogen);
- (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.
- Q 1 is 4-hydroxy-4-phenylpiperidino, 4-acetamido-4-phenylpiperidino,
- Q 2 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q 2 is thienyl, imidazolyl, benzo[b]thiophenyl or naphthyl any of which may bear a halo
- Q 2 is biphenylyl; or Q 2 is carbon-linked indolyl which may bear a benzyl substituent at the 1 -position;
- Q 4 is -OR 2 or -NR 3 R 4 ;
- 1,2,3,4-tetrahydroiso-quinolyl which cyclic amino radical may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl.
- R 5 -R 11 are independently selected from hydrogen and (1 -3C)alkyl ; or the N-oxide of the nitrogen in Q 1 ;
- (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.
- a compound of formula I may contains one or more asymmetically substituted carbon atoms and that such a compound may be isolated in optically active, racemic and/or diastereomeric forms.
- a compound may exhibit
- the present invention encompasses any racemic, optically-active, diastereomeric, polymorphic or stereoisomeric form, or mixture thereof, which form possesses NK1 and NK2 antagonist properties, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the NK1 and NK2 antagonist properties by the standard tests known in the art and those described hereinafter. It may be preferred to use the compound of formula I in a form which is characterized as containing, for example, at least 95%. 98% or 99% enantiomeric excess of the form which is of the (S)-configuration at the center indicated by * in formula I.
- R a , R b , R 1 , R 2 , et cetera stand for generic radicals and have no other significance. It is to be understood that the generic terms "(1-3C)alkyl" and
- (1-6C)alkyl include both straight and branched chain alkyl radicals but references to individual alkyl radicals such as “propyl” embrace only the straight chain ("normal") radical, branched chain isomers such as “isopropyl” being referred to specifically.
- a similar convention applies to other generic groups, for example, alkoxy, alkanoyl, et cetera.
- Halo is fluoro. chloro. bromo or iodo.
- Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
- Heteroaryl encompasses a radical of a monocyclic aromatic ring containing five ring atoms, consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen or containing six ring atoms consisting of carbon and one or two nitrogens, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propenylene, trimethylene of tetramethylene diradical thereto, as well as a stable N-oxide thereof.
- Ar is phenyl which may be unsubstituted or may bear a chloro. methyl, methoxy, hydroxy or methylsulfinyl substituent.
- Het is furyl. thienyl, 2-imidazolyl, 1,3,4-oxadiazol-2-yl, pyridyl or pyrimidinyl which ring may be unsubstituted or may bear a chloro, methyl, methoxy, hydroxy, methylsulfinyl,
- aryl is phenyl.
- heteroaryl is furyl, pyridyl, imidazolyl. indolyl or pyrimidinyl.
- halo is chloro or bromo.
- a particular value for (1-3C)alkyl is methyl, ethyl, propyl or isopropyl; for (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; for (1-5C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl; for (1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or isohexyl; and for (1-8C)alkyl is methyl, ethyl, propyl, isopropyl, isopentyl, 1-ethylpropyl, hexyl, isohe
- a particular value for (3-6C)cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl; for (3-7C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl; and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
- a particular value for (3-6C)alkenyl is allyl, 2-butenyl or 3-methyl-2-butenyl.
- a particular value for (1-4C)alkanoyl is formyl, acetyl, propionyl, butyryl or isobutyryl; and for (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl.
- a more particular value for Ar is phenyl which may be unsubstituted or may bear a methoxy, or hydroxy substituent.
- a more particular value for Het is pyridyl or pyrimidinyl which ring may be unsubstituted or may bear a methoxy, hydroxy or
- methylsulfinyl substituent A more particular value for heteroaryl is pyridyl. A more particular value for halo is chloro.
- a more particular value for (1-3C)alkyl is methyl; for (1-4C)alkyl is methyl or ethyl: for (1-5C)alkyl is methyl, ethyl, propyl or isopropyl; for (1-6C)alkyl is methyl, ethyl, propyl. isopropyl. butyl, isobutyl or 1-butyl; and for (1-8C)alkyl is methyl, ethyl, propyl, isopropyl. 1-ethylpropyl or 1-propylbutyl.
- a more particular value for (3-6C)cylcoalkyl is cyclopropyl or cyclopentyl; for (3-7C)cycloalkyl is cyclopropyl or cyclopentyl; and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
- a more particular value for (3-6C)alkenyl is allyl.
- (1-4C)alkanoyl is formyl or acetyl; and for (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl or isobutyryl.
- Q 1 is 4-hydroxy-4-phenylpiperidino
- Q 3 is hydrogen
- Q 4 is benzylamino, 4-phenylpiperidino, 4-methoxybenzylamino, cyclohexylamino,
- Q 1 4-acetamido-4-phenyl-piperidino or 4-hydroxy-4-phenylpiperidino
- Q 2 is 3,4-dichlorophenyl
- Q 4 is
- a particular group of compounds of formula I are compounds wherein Q 1 is a radical of formulae la, lb, Ic. Id, Ie, If, Ig, lh, Ij , Ik Im, In, Ip, Iq, Ir, Iu, Iv, Iw, or Ix.
- a particular group of compounds of formula I are compounds wherein Q 1 is a radical of formulae le. If, Ig, lh, Ij or Ik..
- a particular group of compounds of formula I are compounds of formula III wherein. Q 1 and Q 4 have any of the values defined above.
- a particular group of compounds of formula I are compounds wherein Q 4 is -OR 2 .
- a particular group of compounds of formula I are compounds wherein Q 4 is NR 3 R 4 .
- a more particular group of compounds of formula I are compounds of formula III wherein Q 1 is a radical of formulae le, If, Ig, lh, Ij or Ik.
- a more particular group of compounds of formula I are compounds of formula III wherein. Q 4 is -OR 2 .
- a more particular group of compounds of formula I are compounds of formula III wherein, Q 4 is NR 3 R 4 .
- R bb (CH 2 ) p -C-R bc in which R bb is Ar or Het; p is the integer 0 or 1 ; and R bc is hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR bd (wherein R bd is hydrogen or
- compositions of a compound of formull I include those made with a strong inorganic or organic acid which affords a physiologically acceptable anion, such as, for example, hydrochloric, sulfuric, phosphoric, methanesulfonic, or para-toluenesulfonic acid.
- a compound of formula I may be made by processes which include processes known in the chemical art for the production of structurally analogous heterocyclic compounds. Such processes and intermediates for the manufacture of a compound of formula I as defined above are provided as further features of the invention and are illustrated by the following procedures in which the meanings of generic radicals are as defined above unless otherwise indicated:
- the alkylation may conveniently be carried out under conventional reductive alkylation conditions, for example by the in situ acid-catalyzed formation of an imminium salt, followed by reduction with sodium cyanoborohydride in alcoholic solvent.
- the reaction may be carried out in a suitable solvent at a temperature in the range of -20 to 100 °C, preferably in the range of 0 to 50 °C. Suitable conditions for the alkylation I can be found at Example 9.
- the protecting group then may be removed when the final compound is to be formed.
- a pharmaceutically acceptable salt of a compound of formula I when required, it may be obtained by reacting the compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
- the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of organic chemistry, techniques which are analogous to the synthesis of known, structurally similar compounds and techniques which are analogous to the above described procedures or the procedures described in the Examples.
- the starting materials and the procedures for their preparation are additional aspects of the invention.
- Piperidines of formula Q 1 -H can be pepared from readily available starting materials using known synthetic methods.
- preparations of piperidines of formula Q 1 -H are disclosed in European Patent Applications, Publication Numbers (EPA) 428434, EPA 474561, EPA 512901, EPA 512902, EPA 515240 and EPA 559538, as well as in WO 94/10146, EPA 0625509 and EPA 0630887, WO 95/05377, WO 95/12577, WO 95/15961, EPA 680962, and WO 95/16682..
- EPA European Patent Applications, Publication Numbers
- Compound a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a "Compound”) may be demonstrated by standard tests and clinical studies, including those disclosed in the EPA publications noted above, and those described below.
- Test A The ability of a Compound of the invention to antagonize the binding of SP at the NK1 receptor may be demonstrated using an assay using the human NK1 receptor expressed in Mouse Erythroleukemia (MEL) cells.
- MEL Mouse Erythroleukemia
- the human NK1 receptor was isolated and characterized as described in: B. Hopkins, et al. "Isolation and characterization of the human lung NK1 receptor cDNA" Biochem, Biophys, Res, Comm.. 1991, 180, 1110-1117; and the NK1 receptor was expressed in Mouse Erythroleukemia (MEL) cells using a procedure similar to that described in Test B below.
- NPA Neurokinin A
- Test B Receptor Binding Assay
- MEL Mouse Erythroleukemia
- the selectivity of a Compound for binding at the NK1 and the NK2 receptors may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of NKB in a tissue preparation selective for NK3 receptors.
- the Compounds of the invention demonstrated statistically significant binding activity in Test A and Test B.
- Compounds having at least 25% inhibition at 1 ⁇ m were subject to Ki determination.
- the compound of Example 1 demonstrated a Ki of 30 nanomolar in Test A, and a Ki of 15 nanomolar in Test B.
- ASMSP a Compound of the invention to antagonize the action of the agonist, Ac-[Arg 6 , Sar 9 , Met(O 2 ) 1 1 ]SP(6-11) (designated ASMSP) in a pulmonary tissue
- ASMSP the agonist
- a functional assay which is carried out under conditions similar to those described in: Emonds-Alt. X., et al. "In vitro and in vivo biological activities of Sr 140333. a novel potent non-peptide tachykinin NK 1 receptor antagonist" Eur. J, Pharmacol.. 1993, 250, 403-413; and which is carried out as follows.
- the segments, with intact endothelium, are suspended between stainless steel stirrups and placed in water-jacketed (37.0°C) tissue baths containing physiological salt solution of the following composition (mM): NaCl, 1 19.0; C1 4.6: CaCl 2 , 1.8; MgCl 2 , 0.5; NaH 2 PO 4 , 1.0: NaHCO 3 . 25.0; glucose 11.0; indomethacin 0.005 .to inhibit cyclooxygenase): and dl-propranolol, 0.001 (to inhibit b-adrenergic receptors); gassed continuously with 95% O 2 -5% CO 2 .
- Initial tension placed on each tissue is 2 grams, which is maintained throughout a 0.5 hour equilibration period. Changes in tension are measured on a Grass polygraph via Grass FT-03 force transducers.
- Thiorphan, 1 X 10 -6 M (to inhibit E.C.3.4.24.11), and a selective NK2 antagonist (to inhibit NK 2 receptors) such as for example, an antagonist described in WO 94/148,184,
- EPA 0625509, EPA 0630887. or the antgonist SR48968 (3 X 10" 8 M), are added to the tissue baths along with the test compound or its vehicle 90 minutes before the NK 1 receptor agonist,
- ASMSP Ac-[Arg 6 , Sar 9 , Met(O 2 ) 11 ]SP(6-1 1) (designated ASMSP).
- the K B values are converted to the negative logarithms and expressed as -log molar K B (i.e. pK B ).
- the potency of the agonist is determined at 50% of its own maximum relaxation in each curve.
- the EC5 0 values are converted to negative logarithms and expressed as -log molar EC 50 .
- Maximum relaxation responses to ASMSP are determined by expressing the maximum response to the agonist as a percentage of the relaxation caused by papaverine.
- guinea pigs are killed by a sha ⁇ blow to the back of the head followed by exsanguination.
- the trachea are removed, trimmed of excess tissue (including removal of epithelium) and cut in spiral fashion.
- Each longitudinally cut tracheal segment is suspended as a strip in a water-jacketed (37.5°C) tissue bath containing a physiological salt solution of the following composition (mM): NaCl, 119; KCl 4.6; CaCl 2 , 1.8; MgCl 2 , 0.5; NaH 2 PO 4 , 1; NaHCO 3 , 25; glucose, 11; and indomethacin, 0.005 (to inhibit cyclooxygenase); gassed continuously with 95% O2-%5 CO 2 .
- Initial tension placed on each tissue is 5 g, which is maintained throughout a 0.5 hour equilibration period before addition of other drugs.
- Tissues are challenged once with a single concentration of capsaicin (1 X 10 -6 M) and washed extensively before addition of a selective NK1 antagonist, such as for example ( ⁇ )-CP96345 (3 X 10 -7 M) (to block NK1 receptors) and thiorphan, 1 X 10 -6 M (to block E.C.3.4.24.11).
- a selective NK1 antagonist such as for example ( ⁇ )-CP96345 (3 X 10 -7 M) (to block NK1 receptors) and thiorphan, 1 X 10 -6 M (to block E.C.3.4.24.11).
- Cumulative addition of the NK 2 agonist [ ⁇ -Ala8]-Neurokinin A(4-10) (designated BANK) is begun 35 minutes after addition of thiorphan.
- Test compound is added 120 min before BANK. Potencies of the compounds are evaluated by calculating apparent dissociation constants (K B ) for each concentration tested using the standard equation:
- the K B values are converted to the negative logarithms and expressed as -log molar K B (i.e. pK B ).
- the potency of BANK is determined at 50% of its own maximum response level in each curve.
- the EC 50 values are converted to the negative logarithms and expressed as -log molar EC 50 .
- Maximum contractile responses to BANK are determined by expressing the maximum response to BANK as a percentage of the initial contraction caused by capasacin.
- the Compounds of the invention which were tested demonstrated functional activity in Tests C and D, with a pKB of 5 or greater typically being measured in each test.
- the compound of Example 1 demonstrated a pKB of 5.41 in Test C, and a pKB of 6.10 in Test D.
- NK 1 or NK 2 receptors The activity of a compound as an antagonist of NK 1 or NK 2 receptors also may be demonstrated in vivo in laboratory animals, for example by adapting a routine guinea pig aerosol test described for evaluation of leukotriene antagonists in: Snyder, et al. "Conscious guinea-pig aerosol model for evaluation of peptide leukotriene antagonists" J. Pharmacol, Meth., 1988, 19, 219, which is carried out as follows.
- agonist is administered by aerosol to six conscious guinea pigs simultaneously during each maneuver.
- BANK 3 X 10 -5 M of either, is aerosolized from a Devilbiss Model 25 ultrasonic nebulizer into an air stream entering the chamber at a rate of 2 L/minute.
- Guinea pigs (275 - 400 g) are fasted for approximately 16 hours prior to experimentation.
- Compounds to be evaluated for blockade of effects of ASMSP or BANK or their vehicle (10% PEG400 in saline) are given by p.o.. i.v. or aerosol routes of
- Aerosol challenge with the agonist produces an initial increase in respiratory rate followed by a decrease with early signs of minor involvement of the abdominal muscles.
- the respiratory rate decreases further and the breathing becomes more labored with greater involvement of the abdominal muscles as exposure continues.
- the distinctly recognizable end point is the point where the breathing pattern of the guinea pig is consistently slow, deep, and deliberate, showing marked involvement of the abdominal muscles.
- Time, in seconds, from the onset of aerosol challenge to this end point is determined for each animal by using a stopwatch. The animals generally collapsed after reaching the end point and did not recover from the agonist-induced respiratory distress.
- Antagonists result in an increase in the time to reach the end point. Animals receive the aerosol administration of agonist for a maximum time of 780 seconds.
- Clinical studies to demonstrate the efficacy of a Compound of the invention may be carried out using standard methods.
- the ability of a Compound to prevent or treat the symptoms of asthma or asthma-like conditions may be demonstrated using a challenge of inhaled cold air or allergen and evaluation by standard pulmonary measurements such as. for example.
- FEV 1 force expiratory volume in one second
- FVC force vital capacity
- SP and NKA have been implicated in the pathology of numerous diseases including: rheumatoid arthritis. Alzheimer's disease, oedema, allergic rhinitis, inflamation pain, gastrointestinal-hypermotility, anxiety, emesis, Huntington's Disease, Psycoses, hypertension, migraine, bladder hypermotility and uticaria.
- one feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease in a human or other mammal in need thereof in which SP or NKA is implicated and antagonism of its action is desired.
- Asthma is characterized by both chronic inflammation and hyperresponsiveness of the airways.
- the NK1 receptor is known to mediate inflammation and mucus
- NK1 and NK2 receptors are involved in the control of the tone of bronchial smooth muscle.
- agents capable of antagonizing the actions of SP and NKA, at the NK1 and NK2 receptors, respectively, are capable of reducing both the chronic inflammation and the airway hyperresponsiveness which are symptomatic of asthma. It has been suggested that an antagonist having mixed affinity for NK1 and NK2 could be therapeutically superior to a receptor selective antagonist.
- NK1 and NK2 Receptors Mediated Tachykinin and Resiniferatoxin-induced Bronchospasm in Guinea Pigs
- another feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of asthma in a human or other mammal in need thereof.
- a compound of the invention When used in the treatment of a disease, a compound of the invention is generally administered as an appropriate pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore and a pharmaceutically acceptable diluent or carrier, the composition being adapted for the particular route of administration chosen.
- a composition is provided as a further feature of the invention. It may be obtained employing conventional procedures and excipients and binders, and it may be one of a variety of dosage forms.
- Such forms include, for example, tablets, capsules, solutions or suspensions for oral administration; suppositories for rectal administration; sterile solutions or suspensions for administration by intravenous or intramuscular infusion or injection; aerosols or nebulizer solutions or suspensions for administration by inhalation; or powders together with pharmaceutically acceptable solid diluents such as lactose for administration by insufflation.
- a tablet or capsule containing up to 250 mg (and typically 5 to 100 mg) of a compound of formula I may conveniently be used.
- a compound of formula I will be administered to humans in a daily dose range of, for example, 5 to 100 mg, in a single dose or divided into two to four daily doses.
- a sterile solution or suspension containing up to 10% w/w (and typically 0.05 to 5% w/w) of a compound of formula I may conveniently be used.
- the dose of a compound of formula I to be administered will necessarily be varied according to principles well known in the art taking account of the route of administration and the severity of the condition and the size and age of the patient under treatment.
- the compound of formula I will be administered to a warm-blooded animal (such as man) so that a dose in the range of, for example, 0.01 to 25 mg/kg (and usually 0.1 to 5 mg/kg) is received.
- a pharmaceutically acceptable salt of a compound of formula I may be used.
- temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is. at a temperature in the range of 18-25 °C;
- chromatography means flash chromatography on silica gel: thin layer chromatography (TLC) was carried out on silica gel plates;
- melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described;
- polymorphism may result in isolation of materials with different melting points in some preparations
- NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using deuterated chloroform (CDCI 3 ) as solvent;
- Mass spectra were run using an automated system with atmospheric pressure chemical ionization (ApCI). Methanol mobile phase enters the probe were it is pneumatically converted into an aerosol and rapidly heated into the gas phase at the probe tip. Hot gas from the probe enters the heated volume of the source which contains the corona discharge pin typically maintained at 3 kV. Methanol molecules rapidly react with ions from the corona discharge to produce stable reagent ions. Analyte molecules introduced into the mobile phase react with the reagent ions at atmospheric pressure and typically become protonated (for positive ions) or deprotonated (for negative ions).
- Example 2 1-[5-(4-hydroxy-4-phenylpiperidino)-3-(3,4-dichloro-phenyl)valeryl]-4-phenylpiperidine hydrochloride salt.
- the intermediate amides used in Examples 3-8 were prepared using a sequence similar to that described in Example 1 and the sub-parts thereof, except replacing the benzylamine used therein with the requsite amine.
- Benzyl 3-(3,4-dichlorophenyl)-5-oxopentanoate (0.850 g) was added to a solution of 4-acetamido-4-phenylpiperidine (0.58 g) in methanol (20 mL) and stirred for 5 minutes.
- Sodium cyanoborohydride (0.157 g) was added and the mixture adjusted to pH 5 by the addition of 5 drops of glacial acetic acid. The mixture was stirred at room temperature for 1.5 hours, and was evaporated. The resulting material was diluted with ethyl acetate, washed (saturated sodium bicarbonate, brine), dried, and evaporated to afford an oil.
- Benzyl 3-(3,4-dichlorophenyl)-2-propenoate 3-(3,4-dichlorophenyl)-2-propenoic acid (20.0 g) was suspended in thionyl chloride (60 mL) and heated at reflux for 2 hours. The mixture was evaporated and the residue dissolved in dichloromethane (100 mL). To this solution was added benzyl alcohol (10.9 g) at 0 °C. The mixture was stirred at room temperature for 2 hours, diluted with an additional 100 mL of dichloromethane and washed with 1M HCl (100 mL), 1M NaOH (150 mL) and brine (100 mL). The organic phase was dried and evaporated.
- the intermediate 5-(4-acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)pentanoic acid was prepared as follows. a. 5-(4-Acetamido-4-phenylpiperidino)-3-(3 ,4-dichlorophenyl)pentanoic acid.
- the intermediate 5-(4-acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)pentanoic acid can crizly be prepared as follows. b. 5-(4-Acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)pentanoic acid.
- the intermediate 5-(4-acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)pentanoic acid is also a compound of the invention.
- Example 16 4- Acetamido-1-[3-(3,4-dichlorophenyl)-4-(1,2,3,4-tetrahydroisoquinol-2-ylcarbonyl)butyl]-4-phenylpiperidine.
- Solvent 1 0.1% trifluoroacetic acid in water
- Solvent 2 0.1% trifluoroacetic acid in acetonitrile
- Solvent 3 1 mM triethylamine in water
- Solvent 4 1 mM triethylamine in acetonitrile
- Solvent A linear gradient : time 0 minutes. 5:95 (Solvent 4:Solvent 3); time 3.0 minutes, 5:95 (Solvent 4:Solvent 3); time 17.0 minutes, 95:5 (Solvent 4; Solvent 3); time 18 minutes, 5:95 (Solvent 4:Solvent 3).
- Solvent B linear gradient: time 0 minutes, 75:25 (Solvent 2:Solvent 1); time 17.0 minutes, 75:25 (Solvent 2; Solvent 1); time 18 minutes, 95:5 (Solvent 2:Solvent 1); time 20 minutes, 75:25 (Solvent 2: Solvent 1).
- Example 55 N-methyl-N-(2-methoxybenzyl)-3-(3,4-dichlorophenyl)-5-(4-(2-methyl-sulfinylphenyl)piperidino)pentanamide hydrochloride salt.
- the product of the reaction was separated by high performance liquid chromatography on a CHIRACEL OD column (17.5 cm ⁇ 20 mm), with hexane:ethanol as the mobile phase, at a flow rate of 9 mL/minute. with UV detection (220 nm).
- the first diasteromer to elute from the column is described in Example 66 and the second to elute is described in Example 67.
- Example 96, Q 4 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl; MS:
- Example 164 5-(4-Acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)-N-[3,5- bis(trifluoromethyl)benzyl]pentanamide. Using a procedure similar to that described in Example 1, except replacing ethyl 5-(4-hydroxy-4-phenylpiperidino)-3-(3,4-dichlorophenyl)pentanoate with ethyl
- Example 171 (R*)-5-(4-Acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)-N-(2-methoxybenzyl)-N-methylpentanamide.
- a racemic mixture of the ethyl ester of Example 15 was resolved by high performance liquid chromatogyaphy using a Chiracel OD (50mm ⁇ 50 cm ) column, with hexane:ethanol (50:50) as the eluent and a flow rate of 54 mL/minute.
- the first ester enantiomer to elute had a retention time of 14 minutes. This ester was hydrolysed under standard conditions to give the corresponding acid.
- the acid was used for the coupling reaction in Example 169.
- the second ester enantiomer to elute had a retention time of 19 minutes. This ester was hydrolysed under standard conditions to give the corresponding acid.
- the acid was used for the coupling reaction in Example 170.
- Example 173 5-[4-(2-Oxoperhydropyrimidin-1-yl)piperidino]-3-(3,4-dichlorophenyl)-N-(2-methoxybenzyl)-N-methylpentanamide.
- 3-(3,4-Dichlorophenyl)-N-(2-methoxybenzyl)-N-methyl-5-oxopentanamide (0.1 molar in tetrahydrofuran, 5 mL) was added through a syringe to 2-oxoperhydropyrimidin-1- ylpiperidine (0.5 mmol) and the mixture was pulse-vortexed for 30 seconds. Glacial acetic acid (0.7 mmol) was added and the solution was allowed to stir for 10 minutes at room temperature. A solution of sodium cyanoborohydride in methanol (0.08 molar. 10 mL) was added in 4 portions with pulse-vortexing between each addition.
- Example 178 3-(3,4-Dichlorophenyl)-5-(4-hydroxy-4-phenylpiperidino)-N-methyl-N-(2-methylphenyl)pentanamide.
- Example 179 4-Acetamido-1-[3-(3,4-dichlorophenyl)-4-(N-(2-methoxybenzyl)-N-methylaminocarbonylbutyl]-1-methyl-4-phenylpiperidinium iodide.
- N-Methyl-N-2-(methoxybenzyl)-5-(4-acetamido-4-phenylpiperidino)-3-(3,4-dichlorophenyl)pentanamide (the compound of Example 10, 0.075 g) was dissolved in dichloromethane (5 mL). Iodomethane (71 mg) was added. After 2 days at room
- Example 180 4-Acetamido-1-[3-(3,4-dichlorophenyl)-4-(N-(2-methoxybenzyl)-N-methylaminocarbonylbutyl]-4-phenylpiperidine 1-oxide.
- Example 254, Q 1 4-(2-Oxo-2,3-dihydrobenzimidazol-1-yl)piperidino.
- Example 255, Q 1 4-Carbamoyl-4-(N,N-dimethylamino)piperidino.
- Example 256, Q 1 4-Acetamido-4-phenylpiperidino.
- Example 269, Q 1 4-(2-Oxopiperidino)piperidino.
- Example 284, Q 1 4-(2-Oxo-2.3-dihydrobenzimidazol-1-yl)piperidino.
- Example 285, Q 1 4-Carbamoyl-4-(N,N-dimethyl-unino)piperidino.
- Example 286, Q 1 4-Acetamido-4-phenylpiperidino.
- Example 298, Q 1 4-(Methylaminocarbonyl)-4-(2-oxopiperidino)piperidino.
- Example 299, Q 1 4-(2-Oxopiperidino)piperidino.
- Example 313, Q 1 4-Hydroxy-4-phenylpiperidino.
- Example 314, Q 1 4-(2-Oxo-2,3-dihydrobenzimidazol-1-yl)piperidino.
- Example 316, Q 1 4-Acetamido-4-phenylpiperidino.
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Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT96901904T ATE202342T1 (en) | 1995-02-10 | 1996-02-08 | 5-(4-SUBST.-PIPERIDINYL-1)-3-ARYL-PENTOIC ACID DERIVATIVES AS TACHYKININ RECEPTOR ANTAGONISTS |
NZ300994A NZ300994A (en) | 1995-02-10 | 1996-02-08 | 5-(4-substituted-piperidinyl)-3-aryl-pentanoic acid derivatives, preparation and medicaments |
AU46297/96A AU714289B2 (en) | 1995-02-10 | 1996-02-08 | 5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist |
JP8524072A JPH10513191A (en) | 1995-02-10 | 1996-02-08 | 5- (4-Substituted-piperidinyl-1) -3-aryl-pentanoic acid derivatives as tachykinin receptor antagonists |
DK96901904T DK0808303T3 (en) | 1995-02-10 | 1996-02-08 | 5- (4-Subst. Piperidinyl-1) -3-aryl pentanoic acid derivatives as tachykinin receptor antagonists |
MX9705801A MX9705801A (en) | 1995-02-10 | 1996-02-08 | 5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist. |
EP96901904A EP0808303B1 (en) | 1995-02-10 | 1996-02-08 | 5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist |
DE69613457T DE69613457T2 (en) | 1995-02-10 | 1996-02-08 | 5- (4-SUBST.-PIPERIDINYL-1) -3-ARYL-PENTANIC ACID DERIVATIVES AS TACHYKININ RECEPTOR ANTAGONISTS |
FI973283A FI973283A (en) | 1995-02-10 | 1997-08-08 | 5- (4-substituted piperidinyl-1) -3-aryl valeric acid derivatives as tachykinin receptor antagonists |
NO973652A NO973652L (en) | 1995-02-10 | 1997-08-08 | 5- (4-Subst. Piperidinyl-1) -3-aryl pentanoic acid derivatives as tachykinin receptor antagonist |
GR20010401497T GR3036639T3 (en) | 1995-02-10 | 2001-09-18 | 5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9502644.9 | 1995-02-10 | ||
GBGB9502644.9A GB9502644D0 (en) | 1995-02-10 | 1995-02-10 | Heterocyclic derivatives |
Publications (1)
Publication Number | Publication Date |
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WO1996024582A1 true WO1996024582A1 (en) | 1996-08-15 |
Family
ID=10769412
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1996/000259 WO1996024582A1 (en) | 1995-02-10 | 1996-02-08 | 5-(4-subst.-piperidinyl-1)-3-aryl-pentanoic acid derivatives as tachykinin receptor antagonist |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP0808303B1 (en) |
JP (2) | JPH10513191A (en) |
KR (1) | KR19980702030A (en) |
CN (1) | CN1181069A (en) |
AT (1) | ATE202342T1 (en) |
AU (1) | AU714289B2 (en) |
CA (1) | CA2209832A1 (en) |
DE (1) | DE69613457T2 (en) |
DK (1) | DK0808303T3 (en) |
ES (1) | ES2159717T3 (en) |
FI (1) | FI973283A (en) |
GB (2) | GB9502644D0 (en) |
GR (1) | GR3036639T3 (en) |
IL (1) | IL117093A0 (en) |
MX (1) | MX9705801A (en) |
NO (1) | NO973652L (en) |
NZ (1) | NZ300994A (en) |
PT (1) | PT808303E (en) |
WO (1) | WO1996024582A1 (en) |
ZA (1) | ZA961069B (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0758238A1 (en) * | 1994-04-26 | 1997-02-19 | Merck & Co. Inc. | Spiro-substituted azacycles as neurokinin-3 antagonists |
WO1999004794A1 (en) * | 1997-07-25 | 1999-02-04 | Merck & Co., Inc. | Cyclic amine modulators of chemokine receptor activity |
WO1999059972A1 (en) * | 1998-05-15 | 1999-11-25 | Aventis Pharmaceuticals Inc. | Carboxy substituted carboxamide derivatives as tachykinin receptor antagonists |
EP1013276A1 (en) * | 1998-12-23 | 2000-06-28 | Pfizer Inc. | Aminoazacycloalkanes as CCR5 modulators |
WO2000039125A1 (en) * | 1998-12-23 | 2000-07-06 | Pfizer Limited | Piperidines as ccr5 modulators |
WO2000038680A1 (en) * | 1998-12-23 | 2000-07-06 | Pfizer Limited | Azabicycloalkanes as ccr5 modulators |
US6090824A (en) * | 1995-11-17 | 2000-07-18 | Zeneca Limited | Therapeutic neurokinin receptor antagonist compounds |
US6136827A (en) * | 1997-07-25 | 2000-10-24 | Merck & Co., Inc. | Cyclic amine modulations of chemokine receptor activity |
US6316445B1 (en) | 1998-05-15 | 2001-11-13 | Aventis Pharmaceuticals Inc. | Carboxy substituted acylic carboxamide derivatives |
WO2005023810A1 (en) * | 2003-09-10 | 2005-03-17 | Virochem Pharma Inc. | Spirohydantoin compounds and methods for the modulation of chemokine receptor activity |
JP2006501182A (en) * | 2002-07-03 | 2006-01-12 | グラクソ グループ リミテッド | N-benzyl-phenyl-heterocyclyl-propionamide compounds as tachykinin inhibitors and / or serotonin reuptake inhibitors |
WO2006083711A1 (en) * | 2005-02-01 | 2006-08-10 | Eli Lilly And Company | Tachykinin receptor antagonists |
WO2007035156A1 (en) * | 2005-09-21 | 2007-03-29 | Astrazeneca Ab | N-oxo-heterocycle and n-oxo-alkyl quinoline-4-carboxamides as nk-3 receptor ligands |
US7402581B2 (en) | 2003-06-13 | 2008-07-22 | Albireo Ab | Azetidine compounds |
US7964733B2 (en) | 2005-09-21 | 2011-06-21 | Astrazeneca Ab | Alkyl sulfoxide quinolines as NK-3 receptor ligands |
US8106208B2 (en) | 2006-05-18 | 2012-01-31 | Albireo Ab | Benzamide compounds that act as NK receptor antagonists |
US8193208B2 (en) | 2005-09-09 | 2012-06-05 | Purdue Pharma L.P. | Fused and spirocycle compounds and the use thereof |
US8288370B2 (en) | 2005-09-29 | 2012-10-16 | Albireo Ab | Substituted azetidine compounds of formula (I) useful in the treatment of functional gastrointestinal disorders, IBS, and functional dyspepsia |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2100711A1 (en) * | 1970-06-01 | 1972-03-24 | Janssen Pharmaceutica Nv | |
WO1994029309A1 (en) * | 1993-06-07 | 1994-12-22 | Merck & Co., Inc. | Spiro-substituted azacycles as neurokinin antagonists |
US5434158A (en) * | 1994-04-26 | 1995-07-18 | Merck & Co., Inc. | Spiro-substituted azacycles as neurokinin-3 antagonists |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI97540C (en) * | 1989-11-06 | 1997-01-10 | Sanofi Sa | Process for the preparation of therapeutically useful aromatically substituted piperidine and piperazine derivatives |
FR2676054B1 (en) * | 1991-05-03 | 1993-09-03 | Sanofi Elf | NOVEL N-ALKYLENEPIPERIDINO COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
GB9321557D0 (en) * | 1992-11-03 | 1993-12-08 | Zeneca Ltd | Carboxamide derivatives |
GB9310713D0 (en) * | 1993-05-24 | 1993-07-07 | Zeneca Ltd | Aryl substituted heterocycles |
-
1995
- 1995-02-10 GB GBGB9502644.9A patent/GB9502644D0/en active Pending
-
1996
- 1996-01-29 GB GBGB9601722.3A patent/GB9601722D0/en active Pending
- 1996-02-08 NZ NZ300994A patent/NZ300994A/en unknown
- 1996-02-08 DK DK96901904T patent/DK0808303T3/en active
- 1996-02-08 MX MX9705801A patent/MX9705801A/en unknown
- 1996-02-08 EP EP96901904A patent/EP0808303B1/en not_active Expired - Lifetime
- 1996-02-08 KR KR1019970705425A patent/KR19980702030A/en not_active Application Discontinuation
- 1996-02-08 DE DE69613457T patent/DE69613457T2/en not_active Expired - Fee Related
- 1996-02-08 WO PCT/GB1996/000259 patent/WO1996024582A1/en not_active Application Discontinuation
- 1996-02-08 ES ES96901904T patent/ES2159717T3/en not_active Expired - Lifetime
- 1996-02-08 PT PT96901904T patent/PT808303E/en unknown
- 1996-02-08 CA CA002209832A patent/CA2209832A1/en not_active Abandoned
- 1996-02-08 AT AT96901904T patent/ATE202342T1/en not_active IP Right Cessation
- 1996-02-08 JP JP8524072A patent/JPH10513191A/en active Pending
- 1996-02-08 CN CN96193228A patent/CN1181069A/en active Pending
- 1996-02-08 AU AU46297/96A patent/AU714289B2/en not_active Ceased
- 1996-02-09 IL IL11709396A patent/IL117093A0/en unknown
- 1996-02-09 ZA ZA961069A patent/ZA961069B/en unknown
-
1997
- 1997-08-08 NO NO973652A patent/NO973652L/en not_active Application Discontinuation
- 1997-08-08 FI FI973283A patent/FI973283A/en unknown
-
2001
- 2001-09-18 GR GR20010401497T patent/GR3036639T3/en not_active IP Right Cessation
-
2007
- 2007-12-26 JP JP2007341959A patent/JP2008138007A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2100711A1 (en) * | 1970-06-01 | 1972-03-24 | Janssen Pharmaceutica Nv | |
WO1994029309A1 (en) * | 1993-06-07 | 1994-12-22 | Merck & Co., Inc. | Spiro-substituted azacycles as neurokinin antagonists |
US5434158A (en) * | 1994-04-26 | 1995-07-18 | Merck & Co., Inc. | Spiro-substituted azacycles as neurokinin-3 antagonists |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0758238A4 (en) * | 1994-04-26 | 1997-09-03 | Merck & Co Inc | Spiro-substituted azacycles as neurokinin-3 antagonists |
EP0758238A1 (en) * | 1994-04-26 | 1997-02-19 | Merck & Co. Inc. | Spiro-substituted azacycles as neurokinin-3 antagonists |
US6090824A (en) * | 1995-11-17 | 2000-07-18 | Zeneca Limited | Therapeutic neurokinin receptor antagonist compounds |
WO1999004794A1 (en) * | 1997-07-25 | 1999-02-04 | Merck & Co., Inc. | Cyclic amine modulators of chemokine receptor activity |
US6136827A (en) * | 1997-07-25 | 2000-10-24 | Merck & Co., Inc. | Cyclic amine modulations of chemokine receptor activity |
WO1999059972A1 (en) * | 1998-05-15 | 1999-11-25 | Aventis Pharmaceuticals Inc. | Carboxy substituted carboxamide derivatives as tachykinin receptor antagonists |
US6316445B1 (en) | 1998-05-15 | 2001-11-13 | Aventis Pharmaceuticals Inc. | Carboxy substituted acylic carboxamide derivatives |
US7041667B1 (en) | 1998-12-23 | 2006-05-09 | Pfizer, Inc. | CCR5 modulators |
HRP20010468B1 (en) * | 1998-12-23 | 2012-06-30 | Pfizer Inc. | Azabicycloalkanes as ccr5 modulators |
WO2000039125A1 (en) * | 1998-12-23 | 2000-07-06 | Pfizer Limited | Piperidines as ccr5 modulators |
WO2000038680A1 (en) * | 1998-12-23 | 2000-07-06 | Pfizer Limited | Azabicycloalkanes as ccr5 modulators |
EP1013276A1 (en) * | 1998-12-23 | 2000-06-28 | Pfizer Inc. | Aminoazacycloalkanes as CCR5 modulators |
JP2006501182A (en) * | 2002-07-03 | 2006-01-12 | グラクソ グループ リミテッド | N-benzyl-phenyl-heterocyclyl-propionamide compounds as tachykinin inhibitors and / or serotonin reuptake inhibitors |
US7402581B2 (en) | 2003-06-13 | 2008-07-22 | Albireo Ab | Azetidine compounds |
US7351713B2 (en) | 2003-09-10 | 2008-04-01 | Viro Chem Pharma, Inc. | Spirohydantoin compounds and methods for the modulation of chemokine receptor activity |
WO2005023810A1 (en) * | 2003-09-10 | 2005-03-17 | Virochem Pharma Inc. | Spirohydantoin compounds and methods for the modulation of chemokine receptor activity |
WO2006083711A1 (en) * | 2005-02-01 | 2006-08-10 | Eli Lilly And Company | Tachykinin receptor antagonists |
US8193208B2 (en) | 2005-09-09 | 2012-06-05 | Purdue Pharma L.P. | Fused and spirocycle compounds and the use thereof |
US8546417B2 (en) | 2005-09-09 | 2013-10-01 | Purdue Pharma L.P. | Fused and spirocycle compounds and the use thereof |
US8883816B2 (en) | 2005-09-09 | 2014-11-11 | Purdue Pharma L.P. | Fused and spirocycle compounds and the use thereof |
WO2007035156A1 (en) * | 2005-09-21 | 2007-03-29 | Astrazeneca Ab | N-oxo-heterocycle and n-oxo-alkyl quinoline-4-carboxamides as nk-3 receptor ligands |
US7964733B2 (en) | 2005-09-21 | 2011-06-21 | Astrazeneca Ab | Alkyl sulfoxide quinolines as NK-3 receptor ligands |
US8288370B2 (en) | 2005-09-29 | 2012-10-16 | Albireo Ab | Substituted azetidine compounds of formula (I) useful in the treatment of functional gastrointestinal disorders, IBS, and functional dyspepsia |
US8106208B2 (en) | 2006-05-18 | 2012-01-31 | Albireo Ab | Benzamide compounds that act as NK receptor antagonists |
Also Published As
Publication number | Publication date |
---|---|
ZA961069B (en) | 1996-08-12 |
DK0808303T3 (en) | 2001-09-10 |
EP0808303A1 (en) | 1997-11-26 |
GB9601722D0 (en) | 1996-03-27 |
KR19980702030A (en) | 1998-07-15 |
ES2159717T3 (en) | 2001-10-16 |
MX9705801A (en) | 1997-10-31 |
CA2209832A1 (en) | 1996-08-15 |
PT808303E (en) | 2001-11-30 |
JP2008138007A (en) | 2008-06-19 |
IL117093A0 (en) | 1996-06-18 |
JPH10513191A (en) | 1998-12-15 |
FI973283A0 (en) | 1997-08-08 |
AU714289B2 (en) | 1999-12-23 |
DE69613457D1 (en) | 2001-07-26 |
FI973283A (en) | 1997-10-07 |
NZ300994A (en) | 1999-10-28 |
NO973652D0 (en) | 1997-08-08 |
CN1181069A (en) | 1998-05-06 |
EP0808303B1 (en) | 2001-06-20 |
ATE202342T1 (en) | 2001-07-15 |
AU4629796A (en) | 1996-08-27 |
GR3036639T3 (en) | 2001-12-31 |
DE69613457T2 (en) | 2002-04-18 |
NO973652L (en) | 1997-10-08 |
GB9502644D0 (en) | 1995-03-29 |
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