WO2011073316A1 - 4-aryl-butane-1,3-diamides - Google Patents

4-aryl-butane-1,3-diamides Download PDF

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WO2011073316A1
WO2011073316A1 PCT/EP2010/069889 EP2010069889W WO2011073316A1 WO 2011073316 A1 WO2011073316 A1 WO 2011073316A1 EP 2010069889 W EP2010069889 W EP 2010069889W WO 2011073316 A1 WO2011073316 A1 WO 2011073316A1
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methyl
carboxamido
carboxamide
pyrrole
phenylbutan
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PCT/EP2010/069889
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English (en)
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Claudia Betschart
Simona Cotesta
Samuel Hintermann
Jürgen Wagner
Bernard Lucien Roy
Marc Gerspacher
Anette Von Matt
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Novartis Ag
Behnke, Dirk
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Publication of WO2011073316A1 publication Critical patent/WO2011073316A1/fr

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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to 4-aryl-butane-1 , 3-diamides, to their preparation, to their use as medicaments and to medicaments comprising them.
  • Orexins (orexin A OX-A and orexin B/OX-B), which are also known as hypocretins, are neuropeptides. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors, the orexin receptors (also known as hypocretin receptors): known are the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R).
  • Orexin A is a 33 amino acid peptide
  • orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors, the orex
  • the orexin-1 receptor has some selectivity for OX-A, whereas the orexin-2 receptor binds OX-A and OX-B with similar affinity. Orexins regulate states of sleep and wakefulness, opening potentially novel therapeutic approaches for narcolepsy as well as insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-45 1).
  • orexins were found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Still furthermore, orexins were shown to play a role in brain reward function/motivation suggesting usefulness to treat substance-related disorders (Harris A.C. et al, Nature, 2005, 437, 556-559).
  • amyloid beta levels inversely correlate with orexin levels in rodents and humans (brain and/or CSF), and that an orexin receptor antagonist reduces both amyloid beta levels and amyloid plaque load in Alzheimer's transgenic mice, thus suggesting usefulness in the treatment of Alzheimers disease (Kang J.E. et al, Science 2009, 326, 1005-1007).
  • Orexin receptors may have numerous implications in disorders such as
  • sleep disorders e.g. sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome;
  • eating disorders e.g. appetite and taste disorders
  • substance-related disorders e.g. substance abuse, substance dependence and substance withdrawal disorders, such as nicotine withdrawal or narcotics withdrawal;
  • psychiatric neurological and neurodegenerative disorders, e.g. depression; anxiety;
  • addictions obsessive compulsive disorder
  • affective neurosis depressive neurosis
  • anxiety neurosis dysthymic disorder
  • mood disorder sexual dysfunction
  • psychosexual dysfunction psychosexual dysfunction
  • sex disorder schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; Parkinson's disease; ischemic or hemorrhagic stroke; migraine; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex;
  • cardiovascular diseases diabetes; asthma; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich's syndrome; hypophysis diseases, hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; subarachnoid hemorrhage
  • allergies benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; vomiting and nausea; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; urinary bladder incontinence e.g. urge incontinence; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; and
  • Orexin receptor antagonists are considered to be useful in the treatment of a wide range of disorders, in particular sleep disorders, eating disorders and substance-related disorders.
  • preferred compounds should bind potently to the orexin receptors (either as OX1 R or OX2R subtype selective antagonists or as dual OX1 R/OX2R antagonists) whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be sufficiently metabolically stable and possess favorable
  • the ideal drug candidate When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will be able to exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • the compounds of the invention are orexin receptor antagonists and are therefore potentially useful in the treatment of a wide range of disorders, particularly sleep disorders, eating disorders, substance-related disorders and Alzheimers disease.
  • the invention relates to a compound of the formula I
  • Ri is C 1-6 alkyl, C -6 halogenalkyl, C 3 . 7 cycloalkyl or C 3-7 cycloalkyl(C - alkyl);
  • R2, R3, R5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, C ⁇ .
  • R 2 and R 3 together with the carbon atom to which they are bound form a C 3 . 7 cycloalkyl; or R 5 and R 6 together are oxo;
  • R 5 and R 6 together with the carbon atom to which they are bound form a C 3 . 7 cycloalkyl;
  • R 4 is hydrogen or C 1-6 alkyl;
  • A is a group A1 , A2, A3 or A4
  • A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, C 1-6 alkyl, d. 6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • A2a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(Ci -4 alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy;
  • each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 12 independently is halogen; C 1-6 alkyl; C 1-6 halogenalkyl; C 1-6 all ⁇ oxy; or 6 halogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic
  • each R 13 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 3-
  • each R 1 independently is halogen or C 1-6 alkyl, or two R 14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
  • p is 0 or 1 ;
  • Ri5 is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 1-6 alkoxy, or C 1-6 halogenalkoxy;
  • C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ri 6 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 6 independently is d -6 alkyl; C -6 halogenalkyl; C -6 alkoxy; C -6 halogenalkoxy; halogen; cyano; or two R 6 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not
  • Alkyl represents a straight-chain or branched-chain alkyl group, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl;
  • C -6 alkyl preferably represents a straight-chain or branched-chain C -4 alkyl with particular preference given to methyl, ethyl, n- propyl, iso-propyl and tert-butyl.
  • C 2 .6alkyl preferably represents a straight-chain or branched- chain C 2-4 alkyl with particular preference given to ethyl, n-propyl, iso-propyl and tert-butyl.
  • alkyl part of "alkoxy”, “halogenalkyl” and so on shall have the same meaning as described in the above-mentioned definition of “alkyl”, especially regarding linearity and preferential size.
  • C3 -7 cycloalkyl represents a saturated alicyclic moiety having from three to seven carbon atoms. This term refers to groups such as cyclopropyl, cyclobutyl, cyclopentyl and
  • alkylene refers to divalent alkyl group as defined herein, for example methylene, ethylene, n-propylene, / ' so-propylene, n-butylene, sec-butylene, iso- butylene, and terf-butylene.
  • a substituent being substituted "once or more than once", for example as defined for A1 a, is preferably substituted by one to three substituents.
  • Halogen is generally fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.
  • Halogenalkyl groups preferably have a chain length of 1 to 4 carbon atoms and are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1 ,1-difluoro- 2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 1 , 1 ,2,2-tetrafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or 2,2,3,4,4,4-hexafluorobutyl; preferably -CF 3 , -CHF 2 , -CH 2
  • A1b, A3a and/or A3b as a "five- to six- membered monocyclic aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses a C 6 -aromatic hydrocarbon group or a five- to six-membered heterocyclic aromatic ring system.
  • C as a "five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses a C 6 - or C 10 -aromatic hydrocarbon group or a five- to ten-membered heterocyclic aromatic ring system.
  • Polycyclic means preferably bicyclic.
  • fused polycyclic aromatic ring system refers to an aromatic sustituent which consists of multiple, e.g. two, aromatic rings that are fused together.
  • R 12 as a "three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses three- to eight membered monocyclic or bicyclic non- aromatic hydrocarbon groups and non-aromatic heterocyclic ring systems of the same sizes.
  • two R 12 or two R 16 as a "fused five- to seven- membered unsaturated non-aromatic ring system” encompasses five- to seven-membered non-aromatic hydrocarbon and heterocyclic groups which comprise at least one double- bond, which is shared with the aromatic ring system they are fused to.
  • a C 6 - or do-aromatic hydrocarbon group is typically phenyl or naphthyl, especially phenyl.
  • five- to six-membered heterocyclic aromatic ring systems consist of 5 to 6 ring atoms of which 1-3 ring atoms are hetero atoms.
  • heterocyclic ring systems are: imidazo[2,1-b]thiazole, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane, tetrahydrofurane, furazane
  • heterocycles are: imidazo[2,1-b]thiazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, furane, tetrahydrofurane, pyridine, pyrimidine, imidazole or pyrazole.
  • the compounds of formula I exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures or diastereomeric mixtures.
  • further asymmetrical carbon atom(s) may be present in the compounds of formula I and their salts.
  • all optical isomers and their mixtures, including the racemic mixtures, are embraced by the invention.
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute stereochemistry
  • the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.
  • any asymmetric atom (e.g. carbon or the like) of the compound(s) of the invention can be present in racemic or enantiomerically enriched, for example the ( ?)-, (S)- or (Reconfiguration.
  • each asymmetric atom has at least 50 %
  • a compound of the invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • compounds of formula I may occur in various tautomeric forms. All tautomeric forms of the compounds of formula I are embraced by the invention.
  • Compounds of formula I may exist in free form or as a salt. In this specification, unless otherwise indicated, language such as "compound of formula I" is to be understood as embracing the compounds in any form, for example free or acid addition salt form. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I, such as picrates or perchlorates, are also included. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and are therefore preferred. Salts are preferably physiologically acceptable salts, formed by the addition of an acid.
  • the term "pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the invention may be capable of forming acid salts by virtue of the presence of suitable groups, such as amino groups.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid,
  • the pharmaceutically acceptable salts of the invention can be synthesized from a parent compound by conventional chemical methods. Generally, such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.
  • the invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein (1) one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and/or (2) the isotopic ratio of one or more atoms is different from the naturally occurring ratio.
  • compounds of formula (I) wherein (1) one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and/or (2) the isotopic ratio of one or more atoms is different from the naturally occurring ratio.
  • isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • hydrogen such as 2 H and 3 H
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 CI
  • fluorine such as 18 F
  • iodine such as 123 l and 125 l
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P
  • sulfur such as 35 S.
  • isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • the invention also provides pro-drugs of the compounds of the invention that converts in vivo to the compounds of the invention.
  • a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
  • the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001).
  • bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covending bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of
  • lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety).
  • Exemplary prodrugs are, e.g., O-acyl derivatives of alcohols.
  • Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the co-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art.
  • amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the compounds of the invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • Preferred substituents, preferred ranges of numerical values or preferred ranges of the radicals present in compounds of the formula I, IA, IB and the corresponding intermediate compounds are defined below.
  • the definition of the substituents applies to the end-products as well as to the corresponding intermediates.
  • the definitions of the substituents may be combined at will, e.g. preferred substituents R 1 and particularly preferred substituents R 2 .
  • the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
  • One class of compounds of the invention are compounds of formula IA
  • R ⁇ R 2 , R 3 , R 4l R 5 , R 6 , A, B and C are as defined under formula (I).
  • One class of compounds of the invention are compounds of formula IB
  • R ⁇ R 2 , R 3 , R 4 , R 5 , Re, A, B and C are as defined under formula (I).
  • C - alkyl for example, methyl, ethyl or n- propyl. In one class of compounds of the invention, is methyl.
  • R 2 , R 3 , R 5 and R 6 are each independently selected from hydrogen, halogen, and C -4 alkyl. In one class of compounds of the invention, R2, R3, R5 and R 6 are each hydrogen.
  • R is hydrogen or C -4 alkyl. In one class of compounds of the invention, R is hydrogen. ln one class of compounds of the invention, A is a ring system selected from A1 , A2, A3 or
  • A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, C h alky!, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C -4 alkyl), C -6 alkoxy, or C 1-6 halogenalkoxy;
  • A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, C ⁇ halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C 1 4 alkyl), C 1 6 alkoxy, or C 1 6 halogenalkoxy;
  • each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ru, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Ru independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 12 independently is halogen; C 1-6 alkyl; Ci -6 halogenalkyl; C 1-6 alkoxy; or d.
  • ehalogenalkoxy or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C 1-4 alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by Ri 3 , and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R 12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may
  • each R 13 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • each Ru independently is halogen or Ci -6 alkyl, or two R 4 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
  • A is A1
  • A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, C h alky!, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 3 .
  • each R 7 or R 8 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • A is A2
  • A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by Ri 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3; each R 9 or R 0 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 . 7 cycloalkyl(Ci -4 alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C -4 alkyl or C 1-4 halogenalkyl.
  • A is A2
  • A2a is a five-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C -6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C - alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • A is A2
  • A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; n is 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, Ci -6 halogenalkyl, C 3 -7cycloalkyl, C 3- 7 cycloalkyl(Ci. 4 alkyl), C -6 alkoxy, or Ci -6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • A is A2
  • A2a is a five-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system is substituted two or three times by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, Ci -6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C 1-4 alkyl), d -6 alkoxy, or C 1-6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • A is A3
  • each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each Rn independently is halogen, C h alky!, C 1-6 halogenalkyl, C 3 - 7 cycloalkyl, C 3 .
  • each Rn independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • A is A3
  • A3a is phenyl which may be substituted once or more than once by Rn;
  • A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to
  • hetero atoms selected from nitrogen, oxygen and sulfur wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Rn independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 3-
  • each Rn independently is halogen, C -4 alkyl or C 1-4 halogenalkyl.
  • A3a is unsubstituted and each Rn independently is halogen, C 1- alkyl or Ci.
  • A is A3 which is biphenyl which may be substituted once or more than once by Rn.
  • each Rn independently is halogen, C ⁇ alkyl or C 1- halogenalkyl.
  • A is A3 which is unsubstituted biphenyl.
  • A is A3
  • A3a is phenyl which may be substituted once or more than once by R ;
  • A3b is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Rn independently is halogen, C 1-6 alkyl, C -6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C 1- alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy.
  • each R independently is halogen, Ci. 4 alkyl or C -4 halogenalkyl.
  • A3a is unsubstituted and each Rn independently is halogen, C 1-4 alkyl or d.
  • A is A4
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by Ri 2 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 12 independently is halogen; C 1-6 alkyl; C 1-6 halogenalkyl; C 1-6 alkoxy; or Ci_
  • ehalogenalkoxy or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C -4 alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by Ri 3 , and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two Ri 2 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-mem bered unsaturated non-aromatic ring system which
  • each R 3 independently is halogen, C -6 alkyl, C -6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • each R 14 independently is halogen or C 1-6 alkyl, or two R 14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
  • A is A4
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 12 independently is halogen; C -6 alkyl; C 1-6 halogenalkyl; C ⁇ alkoxy; or C -6 halogenalkoxy.
  • A4a is a five-membered monocyclic aromatic ring system and each R 12 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, or C ⁇ alkoxy. In one embodiment of said class, A4a is a six-membered monocyclic aromatic ring system and each R 12 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl or C 1-4 alkoxy.
  • p 0.
  • p is 1.
  • p is 1 and Ri 5 is halogen or C 1- alkyl.
  • C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ri 6 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Ri 6 independently is C 1-6 alkyl; C 1-6 halogenalkyl; C 1-6 alkoxy; C 1-6 halogenalkoxy; halogen; cyano; or two R 16 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non-aromatic ring system may in turn be substituted once or more than once by R 17 , and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen; each R 17 independently is halogen or C 1-6 alkyl, or two R 17 at the same ring atom of the fused unsatur
  • C is phenyl, which may be substituted once or more than once by R 16 .
  • each R 16 independently is C 1-6 alkyl; C 1-6 halogenalkyl; C -6 alkoxy; C 1-6 halogenalkoxy; halogen or cyano.
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 .
  • each R 16 independently is halogen, C - alkyl, 4 halogenalkyl, or C M alkoxy.
  • C is pyridyl, for example 2-, 3- or 4-pyridyl, and each R 16 independently is halogen, C 1- alkyl, C 1- halogenalkyl, or C 1- alkoxy.
  • C is unsubstituted 2-pyridyl.
  • C is pyrrolyl, for example 1-, 2- or 3-pyrrolyl, and each R 16 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl. In one embodiment of said class, C is 1-methyl-1H-pyrrol-2-yl.
  • C is an eight- to ten-membered bicyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 .
  • C is C1
  • Ri 6a is C 1- alkyl, for example methyl.
  • One class of compounds of the invention are compounds of formula IA
  • Ri is C 1-4 alkyl and R 2 , R3, R 4 , R 5 and R 6 are each hydrogen;
  • A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, Ci. 4 alkyl or C ⁇ halogenalkyl;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by Ri 6 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R 2 , R3, R4, R5 and R 6 are each hydrogen;
  • A2a is a five- or six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-4 alkyl or C 1- halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R is d. 4 alkyl and R 2 , R3, R , R5 and R 6 are each hydrogen;
  • A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or Ri 0 independently is halogen, Ci. 4 alkyl or Ci. 4 halogenalkyl;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 16 independently is halogen, C 1- alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R 1 is Ci -4 alkyl and R 2 , R3, R , R5 and R 6 are each hydrogen;
  • A is A3
  • A3a is phenyl which may be substituted once or more than once by R ;
  • A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Rn independently is halogen, C 1-4 alkyl or d ⁇ halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R 2 , R3, R 4 , R 5 and R 6 are each hydrogen;
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Ri2 independently is halogen, or C 1-4 alkoxy
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each Ri6 independently is halogen
  • One class of compounds of the invention are compounds of formula IB
  • R is Ci -4 alkyl and R 2 , R 3 , R 4 , Rs and R 6 are each hydrogen;
  • A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 7 or R 8 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6 ;
  • each R 6 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IB
  • R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen;
  • A2a is a five- or six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or Ri 0 independently is halogen, C ⁇ alkyl or C halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C -4 halogenalkyl.
  • ne class of compounds of the invention are compounds of formula IB
  • Ri is C -4 alkyl and R 2 , R3, R4, R5 and R 6 are each hydrogen;
  • A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C -4 alkyl or
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6 ;
  • each R 16 independently is halogen, C 1- alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IB
  • R 2 , R3, R 4 , R5 and R 6 are each hydrogen;
  • A3a is phenyl which may be substituted once or more than once by Rn ;
  • A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R11 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R16 independently is halogen, C 1-4 alkyl or n, are compounds of formula IB
  • Ri is C 1-4 alkyl and R 2 , R3, R 4 , R5 and R 6 are each hydrogen;
  • A is A4
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by Ri 2 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 12 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl or alkoxy;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 6 independently is halogen, C 1-4 alkyl, C -4 halogenalkyl or C 1-4 alkoxy.
  • the invention provides a compound selected from
  • the invention also provides a process for the production of compounds of the formula I.
  • Compounds of the formula I are obtainable according to the following process as described in scheme 1 :
  • Step 1 A compound of formula III, in which R 2 , R 3 , R 4 , R 5 , R 6 and B are as defined under formula I, and R a is C ⁇ alkyl, preferably tert-butyl, may be obtained by reacting a compound of formula II, in which R 2 , R 3 , R 4 , R 5 , Re and B are as defined under formula I, and R a is as defined under formula III, in a first step with methanesulfonyl chloride in the presence of a base, such as triethylamine, in the presence of a suitable solvent, e.g. dichlormethan. The resulting product may then be reacted with sodium cyanide in the presence of a suitable solvent, e.g. dimethylformamide.
  • a base such as triethylamine
  • Step 2 A compound of formula IV, in which R 2 , R 3 , R , R5, Re and B are as defined under formula I, and R a is as defined under formula III, may be obtained by reacting the compound of formula III with a compound of formula V, in which Ri is as defined under formula I, and X c is iodide, in the presence of sodium hydride in the presence of a suitable solvent, e.g. dry tetrahydrofurane.
  • a suitable solvent e.g. dry tetrahydrofurane.
  • Step 3 A compound of formula VI, in which R 1 f R 2 , R 3 , R4, R5, Re and B are as defined under formula I, and R a is as defined under formula III, may be obtained from the compound of formula IV by reduction with e.g. hydrogen/Raney nickel.
  • Step 4 A compound of formula VII, in which Ri, R 2 , R 3 , R4, R5, R 6 , B and C are as defined under formula I, and R a is as defined under formula III, may be obtained by reacting the compound of formula VI with an acid or acid derivative of formula VIII, in which C is defined under formula I, and X is hydroxyl or halogen under suitable reaction conditions as described in the Examples. E.g., when X is halogen in the presence of a suitable base and solvent.
  • Step 5 A compound of formula IX, in which R ⁇ R 2 , R 3 , R , R5, Re, B and C are as defined under formula I, may be obtained by reacting the compound of formula VII with hydrochloric acid in a suitable solvent, e.g. dichlormethane and dioxane.
  • Step 6 A compound of formula I, may be obtained by reacting the compound of formula IX with an acid or acid derivative of formula X, in which A is defined under formula I, and X is hydroxyl or halogen as described in step 4.
  • Step 7 A compound of formula XI, in which R 2 , R 3 , R 4 , R 5 , R 6 and B are as defined under formula I, may be obtained from a compound of formula IV as described in step 5.
  • Step 8 A compound of formula XII, in which Ri, R 2 , R 3 , R 4 , R 5 , R 6 and B are as defined under formula I, may be obtained by reacting the compound of formula XI with a compound of formula X as described in step 6.
  • Step 9 A compound of formula XIII, in which Ri, R 2 , R 3 , R 4 , R 5 , R 6 , A and B are as defined under formula I, may be obtained from the compound of formula XII by reduction as described in step 3.
  • Step 10 A compound of formula I, may be obtained by reacting the compound of formula XIII with a compound of formula VIII as described in step 4.
  • the reactions can be effected according to conventional methods, for example as described in the Examples.
  • Acid addition salts may be produced from the free bases in known manner, and vice-versa.
  • the starting materials of the formulae II, V, VIII and X are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples. In some cases, an intermediate of scheme 1 may be known. In such a situation, said intermediate could be used as an alternative starting point for the process according to scheme 1.
  • the invention also provides a process for the production of compounds of the formula I, in which R 1 t R 2 , R3, R4, R 5 , R 6 , A, B and C are as defined under formula I, which comprises
  • the invention also provides a process for the production of compounds of the formula I, in which Ri , R 2 , R3, R4, R5, Re, A, B and C are as defined under formula I, which comprises
  • A is as defined under formula I, and X is halogen, in the presence of a suitable base and a suitable solvent.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions.
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
  • the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with carrier.
  • Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. orexin receptor modulating properties, e.g. as indicated in in-vitro and in-vivo tests as provided in the next sections and are therefore indicated for therapy.
  • pharmacological properties e.g. orexin receptor modulating properties, e.g. as indicated in in-vitro and in-vivo tests as provided in the next sections and are therefore indicated for therapy.
  • Preferred compounds of the invention show an inhibition of calcium accumulation in recombinant cells expressing at least one of hOxI R or hOx2R at 10 ⁇ of test compound of at least 10%.
  • compounds of the invention which are described in Tables 1 to 4 as showing an inhibition of calcium accumulation in recombinant cells expressing at least one of hOx1 R or hOx2R at 10 ⁇ of test compound of lower than 10%, are excluded.
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 1 ⁇ .
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 500 nM.
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 100 nM.
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxI R or hOx2R of at least 50 nM.
  • Compounds of the invention may be useful in the treatment of an indication selected from: i) sleep disorders;
  • psychiatric, neurological and neurodegenerative disorders such as depression; anxiety; addictions, obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; Parkinson's disease; ischemic or haemorrhagic stroke; migraine; and neurodegenerative disorder including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex;
  • cardiovascular diseases diabetes; asthma; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumour/adenoma; hypothalamic diseases; Froehlich's syndrome; hypophysis diseases, hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; subarachnoid haemorrhage
  • hyperalgesia pain
  • pain enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; and
  • Compounds of the invention may be especially useful in the treatment of an indication selected from: sleep disorders, eating disorders, substance-related disorders and Alzheimers disease.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • insomnias include insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • Substance-related disorders include substance abuse, substance dependence and substance withdrawal disorders, e.g. nicotine withdrawal or narcotics withdrawal.
  • the invention provides the use of a compound of formula (I) in free form or in pharmaceutically acceptable salt form as a medicament.
  • the invention provides the use of a compound of formula (I) in free form or in pharmaceutically acceptable salt form in therapy.
  • the invention provides a method of inhibiting orexin receptor activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I.
  • the invention provides a method of treating a disorder or a disease in a subject mediated by orexin receptors, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I.
  • a disorder or said disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
  • the invention provides the use of a compound of formula I, for the treatment of a disorder or disease in a subject mediated by orexin receptors.
  • the invention provides the use of a compound of formula I, for the treatment of a disorder or disease in a subject characterized by an abnormal activity of orexin receptors.
  • a disorder or said disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
  • the therapy is selected from a disease which is ameliorated by modulation, preferably antagonism, of orexin receptors.
  • the disease is selected from the afore-mentioned list, suitably sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
  • the invention provides a method of treating a disease which is ameliorated by modulation, preferably antagonism, of orexin receptors comprising administration of a therapeutically acceptable amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form.
  • the disease is selected from the afore-mentioned list, suitably sleep disorders, eating disorders or
  • a therapeutically effective amount of a compound of the invention refers to an amount of the compound of the invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by orexin receptors, or (ii) associated with orexin receptor activity, or (iii) characterized by abnormal activity of orexin receptors; or (2) reducing or inhibiting the activity of orexin receptors; or (3) reducing or inhibiting the expression of orexin receptors.
  • a therapeutically effective amount refers to the amount of the compound of the invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of orexin receptors; or at least partially reducing or inhibiting the expression of orexin receptors.
  • the term "subject" refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a human.
  • the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • treating refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • the pharmaceutical composition or combination of the invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 3 molar and 10 "9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the activity of a compound according to the invention can be assessed by in vitro & in vivo methods described herein.
  • the compound of the invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent.
  • the compound of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
  • Agilent 1100 series, Agilent 1100 DAD, Micromass ZMD; column Waters XBridge C18 2.5 pm; 3 x 30 mm; Agilent 1100 oven: temperature 50°C; binary gradient formed with: A: water + acetonitrile (5 %) + TFA (0.05 %) and B: acetonitrile + TFA (0.05 %); 0 - 1.7 min (linear gradient from 90 % A : 10 % B to 5 % A : 95 % B) at 1.4 ml/min; 1.7 - 2.4 min (isocratic elution with 5 % A : 95 % B) at 1.6 ml/min; 2.4 - 2.45 min (linear gradient from 5 % A : 95 % B to 90 % A : 10 % B) at 2.4 ml/min;
  • Lithium hydroxide (143 mg, 5.96 mmol) was added to a solution of 3-methyl-3H- benzotriazole-4-carboxylic acid methyl ester (380 mg, 1.99 mmol) in methanol (6.5 ml). The mixture was stirred at 60 °C overnight. The solvent was evaporated and the residue was acidified to pH 1 with 1 N HCI solution (6.6 ml). The crystals which fell out of solution were filtered and dried to deliver 130 mg of the title compound (91 %).
  • 6-Amino-4-methyl-nicotinonitrile (1.7 g, 12.8 mmol) was suspended in 4N sodium hydroxid solution and stirred 5 h at 100°C to obtain a clear solution.
  • the reaction mixture was cooled in an icebath and acidified by addition of 4N hydrochloric acid.
  • the precipitate was filtered and washed with little water.
  • the residue was dissolved in MeOH, the solvent evaporated at reduced pressure and the product dried at high vacuum to yield the title compound 1.74 g (90%) as colorless solid.
  • 6-Amino-4-methyl-nicotinic acid (1.7 g, 11.2 mmol) was dissolved in MeOH (23 ml) and cone, sulfuric acid (0.30 ml, 5.6 mmol) was added dropwise. The reaction was heated (bath temperature 85°C) over night. Then, the mixture was diluted with EtOAc, washed with NaHC0 3 - and NaCI-soln., dried (Na 2 S0 ), filtered and concentrated. The residue was crystallized from DCM(MeOH)/diethylether/hexane to give the title compound as yellowish crystals (735 mg, 40%).
  • the reaction mixture was extracted with DCM, the combined organic layers were dried over sodium sulfate, and the solvents were evaporated at reduced pressure.
  • the crude product was purified by chromatography on silica (Flashmaster, hexanes to hexanes/EtOAc 7/3 over 40 min), followed by preparative HPLC (water sunfire C18, 5 ⁇ ; solvent: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; gradient: 15-35% B over 16 min; flow 50 ml/min) to give the product as colorless solid.
  • 6-Methyl-furo[3,2-b]pyridine-5-carbonitrile (290 mg, 1.8 mmol) was dissolved in EtOH (12 ml) and potassium hydroxide (1.03 g, 18 mmol) in water (3.3 ml) was added. The reaction was heated at reflux temperature for 20 h. The solvents were evaporated at reduced pressure and the residue was dissolved in water (6.5 ml) and acidified with acetic acid (1.5 ml). The aqueous solution was extracted with EtOAc, the organic layer dried over sodium sulfate and the solvent was evaporated at reduced pressure to give the crude product as brown oil (215 mg, 66%, ⁇ 50% purity) which was used without further purification for the next steps.
  • the HCI salt was dissolved in DCM and washed with sat. NaHC0 3 and NaCI-solution, dried (Na 2 S0 4 ), filtered and concentrated.
  • the title compound (5.01 g, 95 %) was obtained as a yellow oil.
  • 6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide (250 mg, 0.55 mmol), 1 H-indazole-3-carboxylic acid (108 mg, 0.66 mmol), HOBt (102 mg, 0.66 mmol), EDC x HCI (159 mg, 0.83 mmol), and triethylamine (0.46ml, 3.32 mmol) were dissolved in DCM (10 ml) and stirred at rt for 20 h.
  • Examples 1.9 to 1.102 were prepared or can be prepared in analogy to the methods described for Examples 1.1 to 1.8 using the appropriate starting materials or intermediates.
  • Example 1.23 f S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM ⁇ henylbutan-2-yl)-1H-indole-2-carboxamide

Abstract

L'invention porte sur un composé représenté par la formule (I) : dans laquelle les substituants sont tels que définis dans la description, sous forme libre ou sous forme de sel, sur sa préparation, sur son utilisation comme médicament et sur des médicaments le comprenant.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014015167A3 (fr) * 2012-07-18 2014-03-13 University Of Notre Dame Du Lac Composés anti-infectieux 5,5-hétéroaromatiques
JP2014098156A (ja) * 2011-09-26 2014-05-29 Nitto Denko Corp 増強された太陽光集光効率のための高蛍光性かつ光安定性の発色団
WO2015035117A1 (fr) * 2013-09-06 2015-03-12 Lexicon Pharmaceuticals, Inc. Composés à base de pyrazolo[1,5-a] pyrimidine, compositions les comprenant et leurs procédés d'utilisation
US9394479B2 (en) 2011-10-05 2016-07-19 Nitto Denko Corporation Wavelength conversion film having pressure sensitive adhesive layer to enhance solar harvesting efficiency
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
WO2016162318A1 (fr) * 2015-04-08 2016-10-13 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire, et leurs produits intermédiaires
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
WO2019067623A1 (fr) * 2017-09-27 2019-04-04 The Regents Of The University Of California Composés antiviraux puissants contenant de la pyridine
US10611760B2 (en) 2014-09-03 2020-04-07 C4X Discovery Limited Therapeutic compounds as inhibitors of the orexin-1 receptor
US10696654B2 (en) 2016-01-29 2020-06-30 C4X Discovery Limited Therapeutic compounds
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039051A2 (fr) 1980-04-24 1981-11-04 Merck & Co. Inc. Derivés des acides hydroxamiques de type des N-bases de Mannich servant comme composés de départ pour la biodisponibilité d'agents anti-inflammatoires non-stéroidiques, procédé de préparation et composition pharmaceutique les contenant
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2008087611A2 (fr) * 2007-01-19 2008-07-24 Actelion Pharmaceuticals Ltd Dérivés de pyrrolidine et de piperidine
WO2009022311A2 (fr) * 2007-08-15 2009-02-19 Actelion Pharmaceuticals Ltd Dérivés du 1,2-diamido-éthylène
WO2010086366A1 (fr) * 2009-01-30 2010-08-05 Novartis Ag 4-arylbutane-1,3-diamides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039051A2 (fr) 1980-04-24 1981-11-04 Merck & Co. Inc. Derivés des acides hydroxamiques de type des N-bases de Mannich servant comme composés de départ pour la biodisponibilité d'agents anti-inflammatoires non-stéroidiques, procédé de préparation et composition pharmaceutique les contenant
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2008087611A2 (fr) * 2007-01-19 2008-07-24 Actelion Pharmaceuticals Ltd Dérivés de pyrrolidine et de piperidine
WO2009022311A2 (fr) * 2007-08-15 2009-02-19 Actelion Pharmaceuticals Ltd Dérivés du 1,2-diamido-éthylène
WO2010086366A1 (fr) * 2009-01-30 2010-08-05 Novartis Ag 4-arylbutane-1,3-diamides

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
"The Practice of Medicinal Chemistry", 2001, ACADEMIC PRESS
BUNDGAARD, J. MED. CHEM., 1989, pages 2503
BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
CHEMELLI R.M. ET AL., CELL, vol. 98, 1999, pages 437 - 45 1
HARRIS A.C. ET AL., NATURE, vol. 437, 2005, pages 556 - 559
KANG J.E. ET AL., SCIENCE, vol. 326, 2009, pages 1005 - 1007
SAKURAI T. ET AL., CELL, vol. 92, 1998, pages 573 - 585
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH

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