US20080167344A1 - Indoles - Google Patents
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- Publication number
- US20080167344A1 US20080167344A1 US11/959,573 US95957307A US2008167344A1 US 20080167344 A1 US20080167344 A1 US 20080167344A1 US 95957307 A US95957307 A US 95957307A US 2008167344 A1 US2008167344 A1 US 2008167344A1
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- US
- United States
- Prior art keywords
- alkyl
- halo
- optionally substituted
- alkoxy
- haloalkyl
- Prior art date
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- 0 [1*]N1C([2*])=C(C(=O)N2CCC(N3[Y]CC4=C3C([10*])=C([9*])C([8*])=C4[7*])CC2)C2=C([3*])C([4*])=C([5*])C([6*])=C21 Chemical compound [1*]N1C([2*])=C(C(=O)N2CCC(N3[Y]CC4=C3C([10*])=C([9*])C([8*])=C4[7*])CC2)C2=C([3*])C([4*])=C([5*])C([6*])=C21 0.000 description 14
- HTEXXHGWBCGGJW-UHFFFAOYSA-N CC1=C(C(=O)O)C2=CC=C(Cl)C=C2N1 Chemical compound CC1=C(C(=O)O)C2=CC=C(Cl)C=C2N1 HTEXXHGWBCGGJW-UHFFFAOYSA-N 0.000 description 2
- FYLLNCOGRGJREH-UHFFFAOYSA-N O=C(C1=CNC2=CC(Cl)=CC=C21)N1CCC(N2N=NC3=CC=CC=C32)CC1 Chemical compound O=C(C1=CNC2=CC(Cl)=CC=C21)N1CCC(N2N=NC3=CC=CC=C32)CC1 FYLLNCOGRGJREH-UHFFFAOYSA-N 0.000 description 2
- FCEBVKPCYNPOGV-UHFFFAOYSA-N CC(=O)NCCN1CC(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=C1C=C(Cl)C=C2 Chemical compound CC(=O)NCCN1CC(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=C1C=C(Cl)C=C2 FCEBVKPCYNPOGV-UHFFFAOYSA-N 0.000 description 1
- ZAUKMGXKUOIDBJ-UHFFFAOYSA-N CC1=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C2N1 Chemical compound CC1=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C2N1 ZAUKMGXKUOIDBJ-UHFFFAOYSA-N 0.000 description 1
- XIXJVBADEHRQEX-UHFFFAOYSA-N CCN(CC)C(=O)CN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=C1C=C(Cl)C=C2 Chemical compound CCN(CC)C(=O)CN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=C1C=C(Cl)C=C2 XIXJVBADEHRQEX-UHFFFAOYSA-N 0.000 description 1
- IKNSZPHYLAPIQU-UHFFFAOYSA-N CN(C)C(=O)CN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 Chemical compound CN(C)C(=O)CN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 IKNSZPHYLAPIQU-UHFFFAOYSA-N 0.000 description 1
- GNQOXLCYCSGYAW-UHFFFAOYSA-N CN(C)C(=O)CN1C=C(C(=O)N2CCC(N3C(=O)CC4=C3C=CC=C4)CC2)C2=CC=C(Cl)C=C21 Chemical compound CN(C)C(=O)CN1C=C(C(=O)N2CCC(N3C(=O)CC4=C3C=CC=C4)CC2)C2=CC=C(Cl)C=C21 GNQOXLCYCSGYAW-UHFFFAOYSA-N 0.000 description 1
- QPFWHJIXOWZZKA-UHFFFAOYSA-N CN(C)C(=O)CN1C=C(C(=O)O)C2=CC=C(Cl)C=C21 Chemical compound CN(C)C(=O)CN1C=C(C(=O)O)C2=CC=C(Cl)C=C21 QPFWHJIXOWZZKA-UHFFFAOYSA-N 0.000 description 1
- ANTDHPJIHSTHBH-UHFFFAOYSA-N CN(C)CCN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 Chemical compound CN(C)CCN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 ANTDHPJIHSTHBH-UHFFFAOYSA-N 0.000 description 1
- BRPZJZGIPUVKFW-UHFFFAOYSA-N CN(C)CCN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 Chemical compound CN(C)CCN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 BRPZJZGIPUVKFW-UHFFFAOYSA-N 0.000 description 1
- OJNOBYVRGLIBEQ-UHFFFAOYSA-N CN(CCN1C=C(C(=O)O)C2=CC=C(Cl)C=C21)C(=O)OC(C)(C)C Chemical compound CN(CCN1C=C(C(=O)O)C2=CC=C(Cl)C=C21)C(=O)OC(C)(C)C OJNOBYVRGLIBEQ-UHFFFAOYSA-N 0.000 description 1
- WUGWCOFVMSPHNA-UHFFFAOYSA-N CN1CCN2C3=CC(Cl)=CC=C3C(C(=O)N3CCC(N4/N=N\C5=CC=CC=C54)CC3)=C2C1 Chemical compound CN1CCN2C3=CC(Cl)=CC=C3C(C(=O)N3CCC(N4/N=N\C5=CC=CC=C54)CC3)=C2C1 WUGWCOFVMSPHNA-UHFFFAOYSA-N 0.000 description 1
- DOERWNDCKVRFQI-UHFFFAOYSA-N CNC(=O)CN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 Chemical compound CNC(=O)CN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 DOERWNDCKVRFQI-UHFFFAOYSA-N 0.000 description 1
- YWYHVRRILIMRRZ-UHFFFAOYSA-N CNC(=O)CN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 Chemical compound CNC(=O)CN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 YWYHVRRILIMRRZ-UHFFFAOYSA-N 0.000 description 1
- TVQDJYSCTFQINL-UHFFFAOYSA-N CNC(=O)CN1C=C(C(=O)N2CCC(N3C(=O)OC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 Chemical compound CNC(=O)CN1C=C(C(=O)N2CCC(N3C(=O)OC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21 TVQDJYSCTFQINL-UHFFFAOYSA-N 0.000 description 1
- XCBBQOZHNBCCTF-UHFFFAOYSA-N CNC(=O)CN1C=C(C(=O)O)C2=C1C=C(Cl)C=C2 Chemical compound CNC(=O)CN1C=C(C(=O)O)C2=C1C=C(Cl)C=C2 XCBBQOZHNBCCTF-UHFFFAOYSA-N 0.000 description 1
- QEDMKGZHLUTROB-UHFFFAOYSA-N CNCCN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21.Cl Chemical compound CNCCN1C=C(C(=O)N2CCC(N3/N=N\C4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21.Cl QEDMKGZHLUTROB-UHFFFAOYSA-N 0.000 description 1
- SDVLQQCEFCSGLB-UHFFFAOYSA-N CNCCN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21.Cl Chemical compound CNCCN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=CC=C(Cl)C=C21.Cl SDVLQQCEFCSGLB-UHFFFAOYSA-N 0.000 description 1
- FHZNNLOECORHNP-UHFFFAOYSA-N CS(=O)(=O)NCCN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=C1C=C(Cl)C=C2 Chemical compound CS(=O)(=O)NCCN1C=C(C(=O)N2CCC(N3C(=O)CC4=CC=CC=C43)CC2)C2=C1C=C(Cl)C=C2 FHZNNLOECORHNP-UHFFFAOYSA-N 0.000 description 1
- CKDOWLCIMOIVKX-UHFFFAOYSA-N O=C(C1=CN(CC2=CC(F)=CC(F)=C2)C2=C1C=CC(Cl)=C2)N1CCC(N2C(=O)CC3=CC=CC=C32)CC1 Chemical compound O=C(C1=CN(CC2=CC(F)=CC(F)=C2)C2=C1C=CC(Cl)=C2)N1CCC(N2C(=O)CC3=CC=CC=C32)CC1 CKDOWLCIMOIVKX-UHFFFAOYSA-N 0.000 description 1
- HFXUTLOHWVAKJV-UHFFFAOYSA-N O=C(C1=CNC2=CC(Cl)=CC=C21)N1CCC(N2C(=O)CC3=CC=CC=C32)CC1 Chemical compound O=C(C1=CNC2=CC(Cl)=CC=C21)N1CCC(N2C(=O)CC3=CC=CC=C32)CC1 HFXUTLOHWVAKJV-UHFFFAOYSA-N 0.000 description 1
- FAXYFOQDAWRIOB-UHFFFAOYSA-N O=C(C1=CNC2=CC(Cl)=CC=C21)N1CCC(N2C(=O)OC3=CC=CC=C32)CC1 Chemical compound O=C(C1=CNC2=CC(Cl)=CC=C21)N1CCC(N2C(=O)OC3=CC=CC=C32)CC1 FAXYFOQDAWRIOB-UHFFFAOYSA-N 0.000 description 1
- IYKRSBWKJJLFDT-UHFFFAOYSA-N O=C(O)C1=CN(CC2=CC(F)=CC(F)=C2)C2=CC(Cl)=CC=C12 Chemical compound O=C(O)C1=CN(CC2=CC(F)=CC(F)=C2)C2=CC(Cl)=CC=C12 IYKRSBWKJJLFDT-UHFFFAOYSA-N 0.000 description 1
- WHQHEMBHJZAHSB-UHFFFAOYSA-N O=C(O)C1=CNC2=CC(Cl)=CC=C21 Chemical compound O=C(O)C1=CNC2=CC(Cl)=CC=C21 WHQHEMBHJZAHSB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- Vasopressin is a 9 amino acid peptide mainly produced by the paraventricular nucleus of the hypothalamus. Three vasopressin receptors, all belonging to the class I G-protein coupled receptors, are known.
- the V1a receptor is expressed in the brain, liver, vascular smooth muscle, lung, uterus and testis, the V1b or V3 receptor is expressed in the brain and pituitary gland, the V2 receptor is expressed in the kidney where it regulates water excretion and mediates the antidiuretic effects of vasopressin.
- vasopressin acts as a neurohormone and stimulates vasoconstriction, glycogenolysis and antidiuresis.
- vasopressin acts as a neuromodulator and is elevated in the amygdala during stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8).
- the V1a receptor is extensively expressed in the brain and particularly in limbic areas like the amygdala, lateral septum and hippocampus which are playing an important role in the regulation of anxiety.
- V1a knock-out mouse show a reduction in anxious behavior in the plus-maze, open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003). “Profound Impairment in Social Recognition and Reduction in Anxiety-Like Behavior in Vasopressin V1a Receptor Knockout Mice.” Neuropsychopharmacology).
- the downregulation of the V1a receptor using antisense oligonucleotide injection in the septum also causes a reduction in anxious behavior (Landgraf, R., R. Gerstberger, et al. (1995). “V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.” Regul Pept 59(2): 229-39).
- the V1a receptor is also mediating the cardiovascular effects of vasopressin in the brain by centrally regulating blood pressure and heart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris (1999). “Endogenous vasopressin modulates the cardiovascular responses to exercise.” Ann N Y Acad Sci 897: 198-211). In the periphery it induces the contraction of vascular smooth muscles and chronic inhibition of the V1a receptor improves hemodynamic parameters in myocardial infarcted rats (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). “Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats.” Eur J Pharmacol 449(1-2): 135-41).
- the present invention provides novel indol-3-yl-carbonyl-piperidine-benzopyrrolone, -benzoxazolone and -benzotriazole derivatives as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use for the treatment of anxiety and depressive disorders and other diseases.
- phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxy or cyano;
- the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the text or in the examples, or by methods known in the art.
- the compounds of formula (I) possess pharmaceutical activity, in particular they are modulators of V1a receptor activity. More particular, the compounds are antagonists of the V1a receptor. Such antagonists are useful as therapeutics in the conditions of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.
- the preferred indications with regard to the present invention are the treatment of anxiety and depressive disorders.
- alkyl refers to a branched or straight-chain monovalent saturated hydrocarbon radical.
- C 1-6 -alkyl denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, the isomeric pentyls and the like.
- a preferred sub-group of C 1-6 -alkyl is C 1-4 -alkyl, i.e. with 1-4 carbon atoms.
- alkylene refers to a linear or branched saturated divalent hydrocarbon radical.
- C 1-6 -alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g. methylene, ethylene, 2,2-dimethylethylene, n-propylene, 2-methylpropylene, 1-methyl-ethylene, 2-methyl-ethylene and the like.
- alkoxy and C 1-6 -alkoxy refer to the group R′—O—, wherein R′ is alkyl or C 1-6 -alkyl as defined above.
- alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and the like.
- a preferred sub-group of C 1-6 -alkoxy, and still more preferred alkoxy groups are methoxy and/or ethoxy.
- thioalkyl and C 1-6 -thioalkyl refer to the group R′—S—, wherein R′ is alkyl or C 1-6 -alkyl as defined above.
- —S(O) 0-2 C 1-6 -alkyl hence refers to the residues —S—C 1-16 -alkyl, —S(O)—C 1-16 -alkyl, and —S(O) 2 —C 1-16 -alkyl wherein C 1-6 -alkyl is as defined above.
- C 1-6 -alkyl substituted by OH is synonymous with “C 1-6 -hydroxyalkyl” or “hydroxyl-C 1-6 -alkyl” and means a C 1-6 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group.
- C 1-6 -alkyl substituted by CN is synonymous with “C 1-6 -cyanoalkyl” or “cyano-C 1-6 -alkyl” and means a C 1-6 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a CN group.
- halo and “halogen” refer to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) with fluorine, chlorine and bromine being preferred.
- C 1-6 -haloalkyl is synonymous with “halo-C 1-6 -alkyl” or “C 1-6 -alkyl substituted by halo” and means a C 1-6 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro.
- C 1-6 -haloalkyl examples include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) as well as those groups specifically illustrated by the examples herein below.
- preferred C 1-6 -haloalkyl groups are difluoro- or trifluoro-methyl or -ethyl.
- C 1-6 -haloalkoxy is synonymous with “halo-C 1-6 -alkoxy” or “C 1-6 -alkoxy substituted by halo” and means a C 1-6 -alkoxy group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro.
- halogenated alkoxy groups are difluoro- or trifluoro-methoxy or -ethoxy.
- C 2-12 -alkenyl denotes a straight-chain or branched hydrocarbon residue of 2 to 12 carbon atoms comprising at least one double bond.
- a preferred sub-group of C 2-12 -alkenyl is C 2-6 -alkyenyl.
- Examples of the preferred alkenyl groups are ethenyl, propen-1-yl, propen-2-yl (allyl), buten-1-yl, buten-2-yl, buten-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as well as those specifically illustrated by the examples herein below.
- 5 or 6 membered heteroaryl means a monovalent aromatic ring of 5 or 6 ring atoms as ring members containing one, two, three or four ring heteroatoms selected from N, O, and S, the rest being carbon atoms, whereby one, two or three heteroatoms are preferred, and one or two heteroatoms are even more preferred.
- heteroaryl moieties include, but are not limited to pyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl. 5 or 6-membered heteroaryl are optionally substituted with one or more substituents.
- optional substitutents include halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -cyanoalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —S(O) 0-2 C 1-6 -alkyl, nitro, hydroxy, cyano, —(C 1-6 -alkylene)-O—C 1-6 -alkyl, —(C 1-6 -alkylene)-O—C 1-6 -haloalkyl, —(C 1-6 -alkylene)-OR′′′, —C(O)OC 1-6 -alkyl, —C(O)C 1-6 -alkyl, —C(O)OR′′′, —C(O)R′′′, —C(O)NR′R′′, —S(O) 2 NR′R′′, —(CH 2 ) x —NR′R
- Preferred substituents are halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, cyano, —CH 2 CN, —CH 2 OCH 3 , —S(O) 2 —C 1-6 -alkyl, C 1-6 -hydroxyalkyl, —NR′C(O)—C 1-4 -alkyl, —C(O)N(C 1-4 -alkyl) 2 , —C(O)NH(C 1-4 -alkyl), —S(O) 2 N(C 1-4 -alkyl) 2 , or —S(O) 2 NH(C 1-4 -alkyl), or those substitutents as specifically indicated herein.
- heterocycloalkyl means a monovalent saturated ring, consisting of one ring of 3 to 7, preferably from 4 to 6 atoms as ring members, including one, two, three or four heteroatoms chosen from nitrogen, oxygen or sulfur, the rest being carbon atoms, whereby one, two or three heteroatoms are preferred, and one or two heteroatoms are even more preferred. It is understood that the number of heteroatoms depends on the ring size, i.e. 3 and 4-membered heterocycloalkyl preferably contain one heteroatom, 5 to 7-membered heterocycloalkyl preferably contain one, two or three heteroatoms, and even more preferably one or two heteroatoms.
- heterocyclic moieties include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous with tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl, each of which is optionally substituted as described herein.
- 3 to 7-membered heterocycloalkyl are optionally substituted with one or more substituents.
- These optional substitutents include halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -cyanoalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —S(O) 0-2 C 1-6 -alkyl, nitro, hydroxy, cyano, —(C 1-6 -alkylene)-O—C 1-6 -alkyl, —(C 1-6 -alkylene)-O—C 1-6 -haloalkyl, —(C 1-6 -alkylene)-OR′′′, —C(O)OC 1-6 -alkyl, —C(O)C 1-6 -alkyl, —C(O)OR′′′, —C(O)R′′′, —C(O)NR′R
- Preferred substituents are halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, cyano, —CH 2 CN, —CH 2 OCH 3 , —S(O) 2 —C 1-6 -alkyl, C 1-6 -hydroxyalkyl, —NR′C(O)—C 1-4 -alkyl, —C(O)N(C 1-4 -alkyl) 2 , —C(O)NH(C 1-4 -alkyl), —S(O) 2 N(C 1-4 -alkyl) 2 , or —S(O) 2 NH(C 1-4 -alkyl), or those substitutents as specifically indicated herein.
- one or more substituents indicates that in principle every position in the aryl (in particular phenyl), heteroaryl, heterocycloalkyl and cycloalkyl residue may bear such a substituent.
- the pentafluorophenyl residue may be mentioned as a preferred example. However, in 5 to 6-membered aromatic rings, one, two, or three substituents are preferred. In 5 to 6-membered saturated rings, one, two three or four substituents are preferred. In 3 to 4-membered rings, one or two substituents are preferred.
- heterocycle in the definition “R′ and R′′, together with the nitrogen to which they are bound form a five- or six-membered heterocycle comprising one or two heteroatoms selected from the group of nitrogen, oxygen and sulfur” means either heterocycloalkyl or partially unsaturated heterocycloalkyl (synonymous with heterocycloalkenyl), which may optionally be substituted with one, two or three substituents selected from halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, and cyano.
- Preferred heterocycles are piperazine, N-methylpiperazine, morpholin, piperidine and pyrrolidine.
- C 3-7 -cycloalkyl denotes a monovalent or divalent saturated carbocyclic moiety consisting of a monocyclic ring containing from 3 to 7 ring carbon atoms.
- Cycloalkyl can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, halogen, amino, unless otherwise specifically indicated.
- Examples of cycloalkyl moieties include optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl as well as those specifically illustrated by the examples herein below.
- “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
- pharmaceutically acceptable acid addition salt or “pharmaceutically acceptable salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
- “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
- the invention further comprises individual optical isomers of the compounds described herein as well as racemic and non-racemic mixtures thereof.
- phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxy or cyano;
- R 1 is hydrogen. However, not all residues R 1 to R 6 shall simultaneously be hydrogen.
- R 1 is C 1-12 -alkyl, optionally substituted with CN or OH; or R 1 is C 2-12 -alkyl, optionally substituted with CN or OH.
- R 1 is C 1-6 -alkyl, optionally substituted with CN or OH; or R 1 is C 2-6 -alkyl, optionally substituted with CN or OH.
- R 1 is C 1-6 -haloalkyl or C 2-12 -alkenyl. In case R 1 is alkenyl, C 2-6 -alkenyl is preferred.
- variable m in —(CR i R ii ) m —R a is 0, 1, 2, 3 or 4.
- m is preferably 1, 2, 3 or 4.
- R a in —(CR i R ii ) m —R a is 5 to 6-membered heteroaryl
- 5- to 6-membered heteroaryl is as defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
- pyridinyl is preferred, in case m is 1, 2, 3 or 4, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, or thiazolyl are preferred. All these residues are optionally substituted as described herein.
- 3- to 7-membered heterocycloalkyl is as defined above, namely oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous with tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl.
- R a is 3- to 7-membered heterocycloalkyl
- oxiranyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl are preferred. All these residues are optionally substituted as described herein.
- R′′′ is 5 to 6-membered heteroaryl
- 5- to 6-membered heteroaryl is as defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl. Pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, or thiazolyl are preferred.
- n in —(CR iii R iv ) n —C(O)R d is 0, 1, 2, 3 or 4.
- R d in —(CR iii R iv ) n —C(O)R d is 5 to 6-membered heteroaryl
- 5- to 6-membered heteroaryl is as defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
- R d is 5- to 6-membered heteroaryl
- optionally substituted pyridinyl is preferred. All these residues are optionally substituted as described herein.
- R d in —(CR iii R iv ) n —C(O)R d is a 3- to 7-membered heterocycloalkyl
- 3- to 7-membered heterocycloalkyl is as defined above, namely oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous with tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl.
- R d is 3- to 7-membered heterocycloalkyl,
- R′′′ is 5 to 6-membered heteroaryl
- 5- to 6-membered heteroaryl is as defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl. Pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, or thiazolyl are preferred.
- R 1 is —S(O) 2 -phenyl, wherein phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxy or cyano.
- Halo, CF 3 , C 1-4 -alkyl, C 1-6 -alkoxy, OCF 3 and cyano are preferred substitutents.
- R 1 is —S(O) 2 —C 1-6 -alkyl, —S(O) 2 N(C 1-6 -alkyl) 2 , or —S(O) 2 NH(C 1-6 -alkyl).
- R 1 together with R 2 forms a 5- to 6-membered heterocycloalkyl moiety fused to the indole core, bearing one or two ring heteroatoms selected from N, S and O, and being optionally substituted by one or more A.
- A is as defined above.
- the optional substituents are selected from C 1-6 -alkyl, halo, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 1-6 -haloalkoxy.
- it is one optional substituent.
- R n in —C(O)R n of R 2 is a 3- to 7-membered heterocycloalkyl
- 3- to 7-membered heterocycloalkyl is as defined above, namely oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous with tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl.
- R n is 3- to 7-membered heterocycloalkyl, piperidinyl, piperazidinyl,
- R 2 of the compounds of formula (I) is hydrogen or C 1-6 -alkyl.
- R 1 together with R 2 of formula (I) forms a 5- to 6-membered heterocycloalkyl moiety fused to the indole core, bearing one or two ring heteroatoms selected from N, S and O, and being optionally substituted by one or more A.
- the optional substituents are C 1-6 -alkyl, halo, C 1-6 -haloalkyl, C 1-6 -alkoxy or C 1-6 -haloalkoxy.
- R 1 together with R 2 of formula (I) forms a 6-membered heterocycloalkyl moiety fused to the indole core, bearing two nitrogen ring heteroatoms, and being optionally substituted by one or more C 1-6 -alkyl, halo, C 1-6 -haloalkyl, C 1-6 -alkoxy or C 1-6 -haloalkoxy.
- R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy or C 1-6 -haloalkoxy.
- R 3 and R 6 of formula (I) are hydrogen.
- R 4 of formula (I) is hydrogen, Cl, F or methyl.
- R 5 of formula (I) is hydrogen, halo, CF 3 , methoxy or —OCF 3 . If R 5 is hydrogen, R 1 is preferably as defined above, however, with the exclusion of hydrogen. In further embodiments, R 5 is halo, CF 3 , methoxy or —OCF 3 . In further embodiments, R 5 is Cl, F or methoxy; in further embodiments, R 5 is Cl.
- R 3 and R 6 are hydrogen, R 4 is hydrogen, F, Cl or methyl, and R 5 is halo, CF 3 , methoxy or OCF 3 .
- R 7 , R 8 , R 9 , R 10 are each independently hydrogen, halo, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy or C 1-6 -haloalkoxy.
- R 7 , R 8 , R 9 , R 10 are each hydrogen.
- the compounds of the invention are those compounds of formula (I-a):
- the compounds of the invention are those compounds of formula (I-b):
- the compounds of the invention are those compounds of formula (I-c):
- One embodiment of the invention encompasses compounds of formula (I)
- phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxy or cyano;
- X is CH 2
- Y is C ⁇ O
- X is O, and Y is C ⁇ O, or
- X—Y is N ⁇ N
- X is O, and Y is C ⁇ O, or
- X—Y is N ⁇ N
- the invention also encompasses methods for the treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders which comprises administering a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), or (Ic).
- the invention also encompasses a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), or (Ic) and a pharmaceutically acceptable carrier.
- the pharmaceutical composition may further comprise at least one pharmaceutically acceptable excipient.
- the compounds of formula (I) of the invention can be manufactured according to a process comprising reacting a compound of formula (II):
- the compounds of formula (I) of the invention can be manufactured according to a process comprising reacting a compound of formula (I-1), wherein R 1 equals H:
- Compounds of formula (I) can be prepared via an amide coupling between an indole 3-carboxylic acid (II) and a compound of formula (III).
- the usual reagents and protocols known in the art can be used to effect the amide coupling.
- Indole 3-carboxylic acids (II) are either commercially available or readily prepared using a procedure described in J. Med. Chem. 1991, 34, 140. Alternatively, they can be prepared following the general scheme C as described hereinafter.
- the compounds of formula (III) are either commercially available or prepared using methods known in the art starting from commercially available materials.
- General scheme A is hereinafter further illustrated with general procedures I and II.
- Compounds of formula (I) with R 1 different from H can be prepared using methods known in the art, e.g. by N-deprotonation of a compound of formula (I-1) (compounds of formula (I) wherein R 1 is H) followed by treatment with an electrophilic reactant R 1 -Z (wherein Z is a leaving group, e.g. halo) which is either commercially available or easily prepared according to methods well known in the art and commercially available starting materials.
- R 1 -Z wherein Z is a leaving group, e.g. halo
- intermediate (V) which can be hydrolysed with an aqueous sodium hydroxide solution to give the 3-carboxylic acid indole derivative (II-1).
- (V) could react with an electrophilic reactant R 1 -Z to give (VI), which is then converted to the corresponding carboxylic acid derivative (TI) with NaH/H 2 O in DMF (see J. Org. Chem., 1993, 10, 2862).
- Intermediate (VI) can alternatively be obtained by treatment of an indole derivative (IV-2) with trifluoroacetic anhydride in a suitable solvent, e.g. DMF, dichloromethane or 1,2-dichloroethane. Addition of a suitable base may be advantageous.
- the compounds of the present invention exhibit V1a activity, which may be detected as described below:
- the human V1a receptor was cloned by RT-PCR from total human liver RNA.
- the coding sequence was subcloned in an expression vector after sequencing to confirm the identity of the amplified sequence.
- Cell membranes were prepared from HEK293 cells transiently transfected with the expression vector and grown in 20 liter fermenters with the following protocol.
- the pellet was resuspended in 12.5 ml Lysis buffer+12.5 ml Sucrose 20% and homogenized using a Polytron for 1-2 min.
- the protein concentration was determined by the Bradford method and aliquots were stored at ⁇ 80° C. until use.
- 60 mg Yttrium silicate SPA beads (Amersham) were mixed with an aliquot of membrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 10 mM MgCl2) for 15 minutes with mixing.
- the present invention also provides pharmaceutical compositions containing compounds of the invention, for example compounds of formulae (I-a) to (1-e), or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
- Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
- the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
- compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
- suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragées and hard gelatine capsules.
- Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
- Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
- Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
- Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
- compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
- a daily dosage of about 10 to 1000 mg per person of a compound of general formula (I) should be appropriate, although the above upper limit can also be exceeded when necessary.
- Capsules of the following composition can be manufactured:
- the active substance, lactose and corn starch can be firstly mixed in a mixer and then in a comminuting machine.
- the mixture can be returned to the mixer, the talc can be added thereto and mixed thoroughly.
- the mixture can be filled by machine into hard gelatine capsules.
- the suppository mass can be melted in a glass or steel vessel, mixed thoroughly and cooled to 45° C.
- the finely powdered active substance can be added thereto and stirred until it has dispersed completely.
- the mixture can be poured into suppository moulds of suitable size, left to cool; the suppositories then can be removed from the moulds and packed individually in wax paper or metal foil.
- the compounds of formula I may be prepared in accordance with the process variants as described above.
- the starting materials described in the Example section are either commercially available or are otherwise known or derived from the chemical literature, for instance as cited below, or may be prepared as described in the Examples section.
- 6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid Using the procedure described for the preparation of 6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid, from 0.50 g of 2-[6-chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide were prepared 0.38 g (76%) of 6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid as a white solid.
- reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography.
- Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid.
- the aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether.
- the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo.
- the combined organic layers were extracted with 300 ml of a 0.5 M aqueous solution of sodium hydroxide.
- the combined aqueous layers were acidified to pH 2 with an ice-cold 4 M aqueous solution of hydrochloric acid at 0-5° C. and extracted with two 400-ml portions of ethyl acetate.
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US5686624A (en) * | 1992-01-30 | 1997-11-11 | Sanofi | 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
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AU2007341377B2 (en) | 2012-03-22 |
US8143281B2 (en) | 2012-03-27 |
MX2009006920A (es) | 2009-07-06 |
PE20081401A1 (es) | 2008-10-24 |
US20080161315A1 (en) | 2008-07-03 |
TW200835491A (en) | 2008-09-01 |
KR20090094395A (ko) | 2009-09-04 |
RU2009124111A (ru) | 2011-02-10 |
AU2007341377A1 (en) | 2008-07-10 |
CA2674133A1 (en) | 2008-07-10 |
AR064546A1 (es) | 2009-04-08 |
EP2125785A1 (en) | 2009-12-02 |
EP2125785B1 (en) | 2011-11-16 |
BRPI0720968A2 (pt) | 2014-03-11 |
US20080161316A1 (en) | 2008-07-03 |
ES2375520T3 (es) | 2012-03-01 |
WO2008080842A1 (en) | 2008-07-10 |
ATE533760T1 (de) | 2011-12-15 |
KR101134255B1 (ko) | 2012-04-12 |
TWI345468B (en) | 2011-07-21 |
CN101583609A (zh) | 2009-11-18 |
JP2010514726A (ja) | 2010-05-06 |
CL2007003831A1 (es) | 2008-07-11 |
NO20092356L (no) | 2009-06-30 |
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