WO2007039389A1 - Isoxazolo derivatives as gaba a alpha5 inverse agonists - Google Patents

Isoxazolo derivatives as gaba a alpha5 inverse agonists Download PDF

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Publication number
WO2007039389A1
WO2007039389A1 PCT/EP2006/066094 EP2006066094W WO2007039389A1 WO 2007039389 A1 WO2007039389 A1 WO 2007039389A1 EP 2006066094 W EP2006066094 W EP 2006066094W WO 2007039389 A1 WO2007039389 A1 WO 2007039389A1
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Prior art keywords
methyl
pyrrole
isoxazole
carboxylic acid
phenyl
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PCT/EP2006/066094
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French (fr)
Inventor
Bernd Buettelmann
Bo Han
Henner Knust
Matthias Heinrich Nettekoven
Andrew William Thomas
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F. Hoffmann-La Roche Ag
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Priority to JP2008531661A priority Critical patent/JP2009508905A/en
Priority to AU2006298867A priority patent/AU2006298867A1/en
Priority to CA002623043A priority patent/CA2623043A1/en
Priority to DE602006003777T priority patent/DE602006003777D1/en
Priority to BRPI0616184-7A priority patent/BRPI0616184A2/en
Priority to EP06793294A priority patent/EP1931661B1/en
Publication of WO2007039389A1 publication Critical patent/WO2007039389A1/en
Priority to IL189762A priority patent/IL189762A0/en

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    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Definitions

  • the present invention is concerned with aryl-isoxazole-4-carbonyl-pyrrole-2-carboxylic acid amide derivatives of formula
  • R 1 is hydrogen, halogen, lower alkoxy, phenyloxy or benzyloxy
  • R 2 is lower alkyl, (CH 2 ) n -O-lower alkyl or phenyl
  • R 3 is hydrogen or lower alkyl
  • R 4 /R 5 are independently from each other hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkynyl or -(CHR) n -aryl, unsubstituted or substituted by halogen, lower alkyl or lower alkoxy
  • non aromatic heterocyclic ring unsubstituted or substituted by one or two substituents, selected from the group consisting of C(O)O-lower alkyl, lower alkyl, lower alkyl substituted by halogen, cycloalkyl, hydroxy, halogen, N(R)C(O)-lower alkyl, -(CH 2 ) n -O-lower alkyl, or by an aromatic heterocyclic ring;
  • R is hydrogen, hydroxy, or lower alkyl, wherein R may be the same or different in case
  • RVR are independently from each other hydrogen or lower alkyl; n is 0, 1, 2, 3 or 4; m is 1, 2 or 3;
  • this class of compounds show high affinity and selectivity for GABA A cc5 receptor binding sites and might be useful as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer's disease.
  • GABA gamma-aminobutyric acid
  • GABA A receptors which are members of the ligand-gated ion channel superfamily
  • GABA B receptors which are members of the G-protein linked receptor family.
  • the GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of ⁇ , ⁇ and ⁇ subunits.
  • Ccl ⁇ 2 ⁇ 2 mimics many effects of the classical type-I BzR subtypes, whereas ⁇ 2 ⁇ 2 ⁇ 2, Cc3 ⁇ 2 ⁇ 2 and ⁇ 5 ⁇ 2 ⁇ 2 ion channels are termed type- II BzR.
  • ⁇ -CCM benzodiazepine receptor inverse agonist
  • ⁇ -CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans.
  • GABA A cc5 receptor partial or full inverse agonist which is relatively free of activity at GABA A ⁇ l and/or cc2 and/or cc3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity.
  • GABA A cc5 inverse agonists which are not free of activity at GABA A ⁇ l and/or cc2 and/or cc3 receptor binding sites but which are functionally selective for cc5 containing subunits.
  • inverse agonists which are selective for GABA A cc5 subunits and are relatively free of activity at GABA A ⁇ l, ⁇ 2 and ⁇ 3 receptor binding sites are preferred.
  • Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
  • the most preferred indication in accordance with the present invention is Alzheimer's disease.
  • lower alkyl denotes a straight- or branched-chain alkyl group containing from 1-7, preferably from 1 - 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
  • lower alkyl, substituted by halogen denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom.
  • preferred groups are CF 3 , CHF 2 , CH 2 F, CH 2 C(CH 3 )F 2 , CH 2 CH 2 F, CH 2 CF 2 H, or CH 2 CF 3 or CF 2 CH 3 .
  • lower alkynyl denotes a straight- or branched-chain carbon group containing from 2-7, preferably from 2 - 4 carbon atoms, and wherein at least one bond is a triple bond.
  • aryl denotes an unsaturated carbon ring, for example a phenyl, benzyl or naphthyl group.
  • a preferred aryl group is phenyl.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl denotes a cyclic alkyl ring, having from 3 to 7 carbon ring atoms, for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • non aromatic heterocyclic ring denotes a cyclic saturated carbon ring, having from one to three heteroaoms, such as N, O or S, for example the following rings: morpholin, thiomorpholin, piperazin, tetrahydropyran, piperidin, pyrrolidin or tetrahydrofuran.
  • aromatic heterocyclic ring denotes an aromatic 5 or 6 membered ring containing from one to three heteroatoms, such as N, O or S atoms.
  • aromatic heterocyclicl rings are pyridine, thiophen, imidazol, furan, oxazol or pyrazin.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • Exemplary preferred are compounds, which have a binding activity (Ki) of lower than 0.01 ⁇ M and are selective for GABA A cc5 subunits and are relatively free of activity at GABA A ⁇ l, cc2 and cc3 receptor binding sites.
  • Preferred compounds of formula I are those, in which R 1 is hydrogen or halogen, R 2 is methyl, ethyl or CH 2 OCH 3 , R 3 is hydrogen or methyl and R 4 and R 5 do not form together with the N atom a heterocyclic ring.
  • preferred compounds from this group are those, wherein R 1 is hydrogen, R 2 is methyl or ethyl, R 3 and R 4 are hydrogen and R 5 is (CR 2 ) n -cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl, for example the following compounds: 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide,
  • Preferred compounds from this group are further those, wherein R 1 is hydrogen, R 2 is methyl or ethyl, R 3 and R 4 are hydrogen and R 5 is (CH 2 ) n -non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, for example the following compounds
  • Preferred compounds from this group are further those, wherein R 1 is Br, R 2 is methyl, R 3 is methyl, R 4 is hydrogen and R 5 is (CH 2 ) n -non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, for example the following compounds 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid (tetrahydro-pyran-4-yl)-amide or
  • Preferred compounds are further those, wherein R 1 is Br, Cl or F, R 2 is methyl or CH 2 OCH 3 , R 3 and R 4 are hydrogen and R 5 is (CH 2 ) n -non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, for example the following compounds
  • Preferred compounds are further those, wherein R 1 is Br, Cl or F, R 2 is methyl, R 3 and R 4 are hydrogen and R 5 is lower alkyl or alkynyl, for example the following compounds
  • Preferred compounds are further those, wherein R 1 is Br, Cl or F, R 2 is methyl, R 3 and R 4 are hydrogen and R 5 is (CR 2 ) n -cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl, for example the following compounds
  • Preferred compounds are further those, wherein R 1 is Cl or F, R 2 is methyl, R 3 and R 4 are hydrogen and R 5 is (CRi) n -OH, for example the following compounds 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-ethyl)-amide or 4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-ethyl)-amide.
  • Preferred compounds are further those, wherein R 1 is Cl or F, R 2 is methyl, R 3 and
  • R 4 are hydrogen and R 5 is (CH 2 ) n -aromatic heterocyclic ring, for example the following compounds 4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
  • Preferred compounds of formula I are further those, in which R 1 is hydrogen or halogen, R 2 is methyl, ethyl or CH 2 OCH 3 , R 3 is hydrogen or methyl and R 4 and R 5 form together with the N atom a heterocyclic ring.
  • R 1 , R 2 , R 4 and R 5 and m are as described above and R 3 is lower alkyl, and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
  • III, IV, V, VII, VIII, IX and X are known compounds or may be prepared according to methods known in the art.
  • a compound of formula I may be prepared as follows: A mixture of a compound of formula IV (commercially available) and SOCl 2 is heated to reflux for about 3 h. After evaporation the residue is added to a mixture of a compound of formula V (commercially available) and AICI 3 in dichloroethane and heated to reflux for about 3 h. After cooling to room temperature and purification a compound of formula VI is obtained.
  • a mixture of a compound of formula VI and IiOH H 2 O in THF, methanol and water is heated to reflux for about 3 h.
  • the mixture is concentrated and purified in conventional manner to obtain a compound of formula II.
  • the desired compound of formula I maybe prepared following the process as described in scheme 1.
  • the compounds of formula I and their pharmaceutically usable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are ligands for GABA A receptors containing the cc5 subunit and are therefore useful in the therapy where cognition enhancement is required.
  • the affinity of compounds at GABA A receptor subtypes was measured by competition for [3H]flumazenil (85 Ci/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors of composition ⁇ l ⁇ 3 ⁇ 2, cc2 ⁇ 3 ⁇ 2, ⁇ 3 ⁇ 3 ⁇ 2 and ⁇ 5 ⁇ 3 ⁇ 2.
  • Radioligand binding assays were carried out in a volume of 200 mL (96- well plates) which contained 100 mL of cell memebranes, [3H]flumazenil at a concentration of 1 nM for ⁇ l, cc2, cc3 subunits and 0.5 nM for cc5 subunits and the test compound in the range of 10- 10 - 3 x 10-6 M.
  • Nonspecific binding was defined by 10-5 M diazepam and typically represented less than 5 % of the total binding.
  • Assays were incubated to equilibrium for 1 hour at 4 0 C and harvested onto GF/C uni- filters (Packard) by filtration using a Packard harvester and washing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, filter-retained radioactivity was detected by liquid scintillation counting. Ki values were calculated using Excel- Fit (Microsoft) and are the means of two determinations.
  • the compounds of the accompanying examples were tested in the above described assay, and all were found to possess a Ki value for displacement of [3H]flumazenil from cc5 subunits of the rat GABA A receptor of 100 nM or less.
  • the compounds of the invention are binding selective for the cc5 subunit relative to the ⁇ l, ⁇ 2 and ⁇ 3 subunit.
  • the compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi- liquid or liquid polyols etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
  • Example A Tablets of the following composition are manufactured in the usual manner:
  • Capsule fill weight 200 The active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelatine capsules.
  • the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 0 C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-fluoro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 3) was synthesized from 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 95% yield as white solid, (m/e): 315.2 (M + ; 100%).
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-Methoxy- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 4) was synthesized from 4-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O.
  • step 1 4-r3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid
  • step 2
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(2-fluoro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 6) was synthesized from 4-[3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 93% yield as white solid, (m/e): 313.3 (M " ; 100%).
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(3-fluoro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 7) was synthesized from 4-[3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 90% yield as white solid, (m/e): 313.3 (M " ; 100%).
  • step 2
  • step 2
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(4- phenoxy-phenyl)-5-methyl-isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid (intermediate 10) was synthesized from 4-[3-(4-phenoxy-phenyl)-5-methyl-isoxazole-4- carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 86% yield as light-yellow solid.
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(4- benzyloxy-phenyl)-5-methyl-isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid (intermediate 11) was synthesized from 4-[3-(4-benzyloxy-phenyl)-5-methyl-isoxazole- 4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 80% yield as light-yellow solid.
  • step 2 4-(3,5-Diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxyric acid methyl ester
  • step 3 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-(3,5- diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 14) was synthesized from 4-(3,5-diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 81% yield as yellow solid.
  • step 1 4-r3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyll-l-methyl-lH-pyrrole-2- carboxylic acid methyl ester
  • step 2
  • step 1 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-2-trichloroacetyl-lH-pyrrole
  • step 2
  • Example 2 According to the procedure described for the synthesis of Example 2 further Aryl- isoxazole-4-carbonyl-pyrrole-2-carboxylic acid amide derivatives have been synthesised from the respective intermediates mentioned in table 1 and the respective amines mentioned in table 1. The compounds are compiled in table 1 and comprise Example 3 to Example 237. Table 1
  • step 2 4-[3-(4-bromophenyl-5- methyl-isoxazole-4-carbonyl)-l ⁇ -pyrrole-2-carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-l- ⁇ -pyrrole-2- carboxylic acid methyl ester and 2-chloro-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 55.0% yield as light brown solid, (m/e): 345.1 (M + ; 100%).
  • step 2 step 2:
  • step 2 According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole- 2-carboxylic acid (intermediate 1), 4-[3-(2-bromo- phenyl)-5-methyl-isoxazole-4-carbonyi]-lH-pyrrole- 2-carboxylic acid (intermediate 16) was synthesized from 4-[3-(2-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole- 2-carboxylic acid methyl ester through saponification with IiOH H 2 O. The title compound was obtained in 88.1% yield as light-yellow solid, (m/e): 374.9 (M + ; 100%).
  • Example 245 4-[5-Methyl-3-(3,4,5-trifluoro-phenyl)-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclop en tylamide
  • Example 251 4-[3-(3-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid cyclobutylamide
  • 5-methyl-3-(3,4-difluoropheny)l-isoxazole-4- carboxylic acid was synthesized from 5-methyl-3-(3,4-difluorophenyl)-isoxazole-4- carboxylic acid ethyl ester (prepared according to: Synthesis 2003; 1347 - 1356) in 25% yield as yellow solid, (m/e) : 240.1 (M+ 1 ; 100%) .
  • step 2
  • Example 252 4-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylmethyl-amide

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Abstract

The present invention is concerned with aryl-isoxazole-4-carbonyl-pyrrole-2-carboxylic acid amide derivatives of formula (I) wherein R1 is hydrogen, halogen, lower alkoxy, phenyloxy or benzyloxy; R2 is lower alkyl, (CH2)n-O-lower alkyl or phenyl; R3 is hydrogen or lower alkyl; R4/R5 are independently from each other hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkynyl or -(CHR)n-aryl, unsubstituted or substituted by halogen, lower alkyl or lower alkoxy, -(CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two lower alkyl groups, -(CH2)n-aromatic heterocyclic rings -(CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl, -(CHR)n-O-lower alkyl, -(CR2)n-OH, -(CHR)n-NR’R', or R4/R5 form together with the N-atom to which they are attached the ring - 8-aza-bicyclo[3.2.1] octane, substituted by hydroxy, or - 3,4-dihydro- lH-isoquinoline, or - a non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of C(O)O-lower alkyl, lower alkyl, lower alkyl substituted by halogen, cycloalkyl, hydroxy, halogen, N(R)C(O)-lower alkyl, -(CΗ2)n-O-lower alkyl, or by an aromatic heterocyclic ring; R is hydrogen, hydroxy, or lower alkyl, wherein R may be the same or different in case of R2; R’/R' are independently from each other hydrogen or lower alkyl; n is O, 1, 2, 3 or 4; m is 1, 2 or 3; and with their pharmaceutically acceptable acid addition salts. It has been found that this class of compounds show high affinity and selectivity for GABA Aα5 receptor binding sites and might be useful as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer's disease.

Description

ISOXAZOLO DERIVATIVES AS GABA A ALPH A5 INVERSE AGONISTS
The present invention is concerned with aryl-isoxazole-4-carbonyl-pyrrole-2-carboxylic acid amide derivatives of formula
Figure imgf000002_0001
wherein
R1 is hydrogen, halogen, lower alkoxy, phenyloxy or benzyloxy; R2 is lower alkyl, (CH2)n-O-lower alkyl or phenyl; R3 is hydrogen or lower alkyl; R4/R5 are independently from each other hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkynyl or -(CHR)n-aryl, unsubstituted or substituted by halogen, lower alkyl or lower alkoxy,
-(CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two lower alkyl groups, -(CH2)n-aromatic heterocyclic rings
-(CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl,
-(CHR)n-O-lower alkyl, -(CRz)n-OH, -(CHR)n-NR5R", or R4/R5 form together with the N-atom to which they are attached the ring - 8-aza-bicyclo[3.2.1] octane, substituted by hydroxy, or
- 3,4-dihydro- lH-isoquinoline, or
- a non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of C(O)O-lower alkyl, lower alkyl, lower alkyl substituted by halogen, cycloalkyl, hydroxy, halogen, N(R)C(O)-lower alkyl, -(CH2)n-O-lower alkyl, or by an aromatic heterocyclic ring;
R is hydrogen, hydroxy, or lower alkyl, wherein R may be the same or different in case
OfR2; RVR" are independently from each other hydrogen or lower alkyl; n is 0, 1, 2, 3 or 4; m is 1, 2 or 3;
and with their pharmaceutically acceptable acid addition salts.
It has been found that this class of compounds show high affinity and selectivity for GABA A cc5 receptor binding sites and might be useful as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer's disease.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion channel superfamily and (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of α, β and γ subunits.
Presently a total number of 21 subunits of the GABA A receptor have been cloned and sequenced. Three types of subunits (α, β and γ) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding site lies between the α and γ subunits. Among the recombinant GABA A receptors, Cclβ2γ2 mimics many effects of the classical type-I BzR subtypes, whereas α2β2γ2, Cc3β2γ2 and α5β2γ2 ion channels are termed type- II BzR.
It has been shown by McNamara and Skelton in Psychobiology, 21:101-108 that the benzodiazepine receptor inverse agonist β-CCM enhance spatial learning in the Morris watermaze. However, β-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A cc5 receptor partial or full inverse agonist which is relatively free of activity at GABA A αl and/or cc2 and/or cc3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A cc5 inverse agonists which are not free of activity at GABA A αl and/or cc2 and/or cc3 receptor binding sites but which are functionally selective for cc5 containing subunits. However, inverse agonists which are selective for GABA A cc5 subunits and are relatively free of activity at GABA A αl, α2 and α3 receptor binding sites are preferred.
Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The most preferred indication in accordance with the present invention is Alzheimer's disease.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a straight- or branched-chain alkyl group containing from 1-7, preferably from 1 - 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
The term "lower alkyl, substituted by halogen"denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom. Examples of preferred groups are CF3, CHF2, CH2F, CH2C(CH3)F2, CH2CH2F, CH2CF2H, or CH2CF3 or CF2CH3.
The term "lower alkynyl" denotes a straight- or branched-chain carbon group containing from 2-7, preferably from 2 - 4 carbon atoms, and wherein at least one bond is a triple bond.
The term "aryl" denotes an unsaturated carbon ring, for example a phenyl, benzyl or naphthyl group. A preferred aryl group is phenyl.
The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "cycloalkyl" denotes a cyclic alkyl ring, having from 3 to 7 carbon ring atoms, for example, cyclopropyl, cyclopentyl or cyclohexyl.
The term "non aromatic heterocyclic ring" denotes a cyclic saturated carbon ring, having from one to three heteroaoms, such as N, O or S, for example the following rings: morpholin, thiomorpholin, piperazin, tetrahydropyran, piperidin, pyrrolidin or tetrahydrofuran.
The term "aromatic heterocyclic ring "denotes an aromatic 5 or 6 membered ring containing from one to three heteroatoms, such as N, O or S atoms. Examples of such aromatic heterocyclicl rings are pyridine, thiophen, imidazol, furan, oxazol or pyrazin.
The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred are compounds, which have a binding activity (Ki) of lower than 0.01 μM and are selective for GABA A cc5 subunits and are relatively free of activity at GABA A αl, cc2 and cc3 receptor binding sites.
Preferred compounds of formula I are those, in which R1 is hydrogen or halogen, R2 is methyl, ethyl or CH2OCH3, R3 is hydrogen or methyl and R4 and R5 do not form together with the N atom a heterocyclic ring.
More specifically, preferred compounds from this group are those, wherein R1 is hydrogen, R2 is methyl or ethyl, R3 and R4 are hydrogen and R5 is (CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl, for example the following compounds: 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide,
4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclobutylamide,
4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclopentylamide, 4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide or 4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclopropylamide.
Preferred compounds from this group are further those, wherein R1 is hydrogen, R2 is methyl or ethyl, R3 and R4 are hydrogen and R5 is (CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, for example the following compounds
4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (tetrahydro- pyran-4-yl)-amide or
4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (tetrahydro- pyran-4-yl)-amide.
Preferred compounds from this group are further those, wherein R1 is Br, R2 is methyl, R3 is methyl, R4 is hydrogen and R5 is (CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, for example the following compounds 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid (tetrahydro-pyran-4-yl)-amide or
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid (3-morpholin-4-yl-propyl)-amide.
Preferred compounds are further those, wherein R1 is Br, Cl or F, R2 is methyl or CH2OCH3 , R3 and R4 are hydrogen and R5 is (CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, for example the following compounds
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide, 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(2,2-dimethyl-tetrahydro-pyran-4-yl)-amide,
4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide,
4-[3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide,
4-[3-(4-fluoro-phenyl)-5-methoxymethyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid (tetrahydro-pyran-4-yl)-amide or
4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide.
Preferred compounds are further those, wherein R1 is Br, Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is lower alkyl or alkynyl, for example the following compounds
4-[3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lΗ-pyrrole-2-carboxylic acid isopropylamide, 4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid prop-2-ynylamide or
4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid prop-2-ynylamide.
Preferred compounds are further those, wherein R1 is Br, Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is (CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl, for example the following compounds
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(4-hydroxy-cyclohexyl)-amide, 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide,
4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylamide,
4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclobutylamide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylamide, 4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide,
4-[3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide,
4-[3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide or
4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide.
Preferred compounds are further those, wherein R1 is Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is (CRi)n-OH, for example the following compounds 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-ethyl)-amide or 4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-ethyl)-amide.
Preferred compounds are further those, wherein R1 is Cl or F, R2 is methyl, R3 and
R4 are hydrogen and R5 is (CH2)n-aromatic heterocyclic ring, for example the following compounds 4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
[2-(lH-imidazol-4-yl)-ethyl] -amide,
4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
( fur an - 2- ylmethyl) - amide,
4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide or
4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
[2-(lH-imidazol-4-yl)-ethyl] -amide.
Preferred compounds of formula I are further those, in which R1 is hydrogen or halogen, R2 is methyl, ethyl or CH2OCH3, R3 is hydrogen or methyl and R4 and R5 form together with the N atom a heterocyclic ring.
The present compounds of formula I and their pharmaceutically acceptable salts may be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula
Figure imgf000009_0001
with an amine of formula
Ff
HN
V III in the presence of TBTU and N,N-diisopropylethylamine
to a compound of formula
Figure imgf000009_0002
wherein R1, R2, R3, R4 and R5 and m are as described above, or b) reacting a compound of formula
Figure imgf000009_0003
with an amine of formula
Ff
HN
V III to a compound of formula
Figure imgf000010_0001
wherein R1, R2, R4 and R5 and m are as described above, c) reacting a compound of formula
Figure imgf000010_0002
with an alkyliodide of formula R3I (for R3 = lower alkyl) to a compound of formula
Figure imgf000010_0003
wherein R1, R2, R4 and R5 and m are as described above and R3 is lower alkyl, and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
The following schemes (scheme 1, 2 and 3) describe the processes for preparation of compounds of formula I in more detail. The starting materials of formulas
III, IV, V, VII, VIII, IX and X are known compounds or may be prepared according to methods known in the art.
Scheme 1
Figure imgf000011_0001
lamine,
Figure imgf000011_0002
In accordance with scheme 1, a compound of formula I may be prepared as follows: A mixture of a compound of formula IV (commercially available) and SOCl2 is heated to reflux for about 3 h. After evaporation the residue is added to a mixture of a compound of formula V (commercially available) and AICI3 in dichloroethane and heated to reflux for about 3 h. After cooling to room temperature and purification a compound of formula VI is obtained.
A mixture of a compound of formula VI and IiOH H2O in THF, methanol and water is heated to reflux for about 3 h. The mixture is concentrated and purified in conventional manner to obtain a compound of formula II.
Further, a mixture of a compound of formula II, an amine of formula III (commercially available), 2-( lH-benzotriazole- 1-yl)- 1,1,3,3-tetramethyluronium tetraflu or ob orate (TBTU) and N,N-disiopropylethylamine in DMF is reacted at room temperature for about 16 h to obtain the desired compound of formula I.
Scheme 2
Figure imgf000012_0001
In accordance with scheme 2, A mixture of a compound of formula VII, a compound of formula VIII (commercially available) and bis(tri-N-butyltin) oxide (commercially available) in toluene is refluxed for about 22 h. After evaporation the residue is purified and concentrated in conventional manner to obtain a compound of formula VI.
The desired compound of formula I maybe prepared following the process as described in scheme 1.
Scheme 3
Figure imgf000013_0001
for R3 is lower alkyl
To a solution of 2-trichloroacetyl- lH-pyrrole (commercially available) in CH2Cl2 and nitromethane AICI3 is added in one portion. Then a compound of formula X in CH2Cl2 is added dropwise. The reaction mixture is stirred at room temperature for about 18 h, concentrated and purified in conventional matter. Then a mixture of the obtained compound of formula XI, an amine of formula III and triethylamine is stirred overnight at about 60 0C. After cooling to room temperature, the reaction mixture is evaporated to dryness to obtain a compound of formula 1-1. To a solution of this compound in dry DMF is added KOt-Bu and the mixture is stirred at room temperature for about 30 minutes. The reaction is cooled to 0 C and methyl iodide is added. The resulting mixture is stirred at room temperature for about 8 h. It is obtained a compound of formula I, wherein R3 is lower alkyl.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are ligands for GABA A receptors containing the cc5 subunit and are therefore useful in the therapy where cognition enhancement is required.
The compounds were investigated in accordance with the test given hereinafter. Membrane preparation and binding assay
The affinity of compounds at GABA A receptor subtypes was measured by competition for [3H]flumazenil (85 Ci/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors of composition αlβ3γ2, cc2β3γ2, α3β3γ2 and α5β3γ2.
Cell pellets were suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mM CaC12, 1.2 mM MgC12, 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized by polytron for ca. 20 sec on ice and centrifuged for 60 min at 4 0C (50000 g; Sorvall, rotor: SM24 = 20000 rpm). The cell pellets were resuspended in Krebs-tris buffer and homogenized by polytron for ca.15 sec on ice. Protein was measured (Bradford method, Bio-Rad) and aliquots of 1 mL were prepared and stored at -80 0C.
Radioligand binding assays were carried out in a volume of 200 mL (96- well plates) which contained 100 mL of cell memebranes, [3H]flumazenil at a concentration of 1 nM for αl, cc2, cc3 subunits and 0.5 nM for cc5 subunits and the test compound in the range of 10- 10 - 3 x 10-6 M. Nonspecific binding was defined by 10-5 M diazepam and typically represented less than 5 % of the total binding. Assays were incubated to equilibrium for 1 hour at 4 0C and harvested onto GF/C uni- filters (Packard) by filtration using a Packard harvester and washing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, filter-retained radioactivity was detected by liquid scintillation counting. Ki values were calculated using Excel- Fit (Microsoft) and are the means of two determinations.
The compounds of the accompanying examples were tested in the above described assay, and all were found to possess a Ki value for displacement of [3H]flumazenil from cc5 subunits of the rat GABA A receptor of 100 nM or less. In a preferred embodiment the compounds of the invention are binding selective for the cc5 subunit relative to the αl, α2 and α3 subunit.
Figure imgf000014_0001
Figure imgf000015_0001
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi- liquid or liquid polyols etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.
Example A Tablets of the following composition are manufactured in the usual manner:
mg/tablet
Active substance 5 Lactose 45
Corn starch 15
Microcrystalline cellulose 34
Magnesium stearate 1
Tablet weight 100
Example B
Capsules of the following composition are manufactured:
mg/capsule
Active substance 10
Lactose 155
Corn starch 30
Talc 5
Capsule fill weight 200 The active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelatine capsules.
Example C
Suppositories of the following composition are manufactured:
mg/supp.
Active substance 15
Suppository mass 1285 Total 1300
The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 450C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. Examples 2, 229 and 230 have been described in detail, the remaining compounds have been prepared accordingly.
Example 2
4-(5-Methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (pyridin-2- ylmethyl)-amide
Figure imgf000018_0001
a) Step 1:
4-(5-Methyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000018_0002
A mixture of 406 mg (2 mmol) 5-methyl-3-phenyl-isoxazole-4-carboxylic acid
(commercially available) and 4 mL SOCl2 was heated to reflux for 3 h. After evaporation of all volatiles the residue was added to a mixture of 206 mg (2 mmol) lH-pyrrole-2- carboxylic acid methyl ester (commercially available) and 440 mg (3 mmol) AICI3 in 25 mL dichloroethane and heated to reflux for 3 h. After cooling to room temperature the precipitate was collected and washed with dichloromethane. The residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 210 mg (37%) of the title compound as white foam, (m/e): 311.0 (MH+; 100%).
b) Step 9. 4-(5-Methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (intermediate
11
Figure imgf000019_0001
A mixture of 1.2 g (4 mmol) 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2- carboxylic acid methyl ester and 1.3 g (31 mmol) IiOH H2O in 40 mLTHF, 5 mL methanol and 10 mL water was heated to reflux for 3 h. The mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to yield 1.1 g (96%) of the title compound as light yellow solid, (m/e): 295.1 (M"; 100%).
c) Step 3:
A mixture of 20 mg (0.67 mmol) 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-lH- pyrrole-2-carboxylic acid (intermediate 1), 11 mg (0.1 mmol) C-pyridin-2-yl- methylamine (commercially available), 32 mg (0.1 mmol) 2-(lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetraflu or ob orate (TBTU) and 26 mg (0.2 mmol) N ,N- disiopropylethylamine in 1.1 mLDMF was reacted at room temperature for 16 h and subsequently subjected to preparative HPLC purification on reversed phase eluting with a acetonitrile / water (0.05% NEt3) gradient. After evaporation of the product fractions 7.6 mg (29%) of the title compound was obtained, (m/e): 387.2 (MH+; 100%)
Intermediate 2
4-[3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000019_0002
a) Step 1:
4-(l-Oxo-but-2-vnyl)-lH-pyrrole-2-carboxyric acid methyl ester
Figure imgf000020_0001
A mixture of 1 g (10 mmol) but-2-ynoyl chloride (Journal of Organic Chemistry (1981), 46(11), 2273-80), 0.625 g (5 mmol) 5-Meώyl-3-phenyl-isoxa∞le-4-carboxylic acid (commercially available) and 1.3 g (10 mmol) AICI3 in 10 mL dichloroethane was at room temperature for 18 h. The mixture was poured onto ice/water and the organic layer washed with Na2CO3 sat., NaCl sat. and dried with Na2SO4. After evaporation of all volatiles the residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 0.2 g (17%) of the title compound as light brown solid, (m/e): 227.1 (M+).
b) Step 2:
4-r3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxyric acid methyl ester
Figure imgf000020_0002
A mixture of 956 mg (5 mmol) 4-( l-oxo-but-2-ynyl)- lH-pyrrole-2-carboxylic acid methyl ester, 3.5 g (15 mmol) 4-bromo-N-hydroxybenzenecarboxymidoyl chloride (commercially available) and 4.47 g (7 mmol) bis(tri-N-butyltin) oxide (commercially available) in 75 mL toluene was refluxed for 22 h. After evaporation of all volatiles the residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 990 mg (51%) of the title compound as light yellow solid, (m/e): 389.3 (M+; 100%).
c) Step 3:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-bromo- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 2) was synthesized from 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 93% yield as white solid, (m/e): 374.8 (M"; 97%).
Intermediate 3 4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000021_0001
a) Step 1:
4-r3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000021_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester was obtained from 4-( l-oxo-but-2-ynyl)- lH-pyrrole-2-carboxylic acid methyl ester and 4-fluoro-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 53.6% yield as light brown solid, (m/e): 329.0 (M+; 100%).
b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-fluoro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 3) was synthesized from 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 95% yield as white solid, (m/e): 315.2 (M+; 100%).
Intermediate 4 4-[3-(4-Methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000022_0001
a) Step 1:
4-r3-(4-Methoxy-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000022_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid methyl ester was obtained from 4-( l-oxo-but-2-ynyl)- lH-pyrrole-2- carboxylic acid methyl ester and 4-methoxy-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 58% yield as light brown solid (m/e): 341.3 (M+; 100%).
b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-Methoxy- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 4) was synthesized from 4-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 85% yield as white solid, (m/e): 325.1 (M"; 100%). In ter mediate 5 4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000023_0001
a) step 1: 4-r3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid
Figure imgf000023_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2-carboxylic acid methyl ester and 4-chloro-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 42% yield as light yellow solid, (m/e): 345.1 (M+; 100%).
b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-chloro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 5) was synthesized from 4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 91% yield as light-yellow solid, (m/e): 331.1 (M+; 100%).
Intermediate 6 4-[3-(2-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000024_0001
a) step 1:
4-r3-(2-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000024_0002
Amixture of 4.07 g (21.3 mmol) 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2-carboxylic acid methyl ester, 18.5 g (106.5 mmol) 2- fluoro-N-hydroxybenzenecarboxymidoyl chloride (commercially available) and 12.7 g (21.3 mmol) Bis(tri-N-butyltin) oxide (commercially available) in 300 mL toluene was refluxed for 22 h. After evaporation of all volatiles the residue was purified on silica eluting with a gradient of ethyl acetate and hexane affording 6.78 g (97 %) of the title compound as light brown solid, (m/e): 329.0 (M+; 100%).
b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(2-fluoro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 6) was synthesized from 4-[3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 93% yield as white solid, (m/e): 313.3 (M"; 100%).
Intermediate 7 4-[3-(3-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000025_0001
a) step 1:
4-r3-(3-Huoro-phenyl)-5-methyl-isoxazole-4-carbonyri-lH-pyrrole-2-carboxyric acid methyl ester
Figure imgf000025_0002
According to the procedure described for the synthesis of 4-[3-(2-fluoro-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 6, step 1), 4-[3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2-carboxylic acid methyl ester and 3-fluoro-N-hydroxybenzenecarboxymidoyl chloride (Bioorganic & Medicinal Chemistry Letters (2003), 13(10), 1795- 1799) in 94% yield as light brown solid (m/e): 329.0 (M+; 100%).
b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(3-fluoro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 7) was synthesized from 4-[3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 90% yield as white solid, (m/e): 313.3 (M"; 100%).
Intermediate 8 4-[3-(3-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000026_0001
a) step 1:
4-r3-(3-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000026_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2-carboxylic acid methyl ester and 3-chloro-N-hydroxybenzenecarboxymidoyl chloride (Bioorganic & Medicinal Chemistry Letters (2003), 13(10), 1795- 1799) in 52% yield as light yellow solid, (m/e): 345.0 (M+; 100%).
b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(3- chloro-phenyl)-5-methyl-isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid (intermediate 8) was synthesized from 4-[3-(3-chloro-phenyl)-5-methyl-isoxazole-4- carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 95% yield as light-yellow solid.
Intermediate 9 4-[3-(3-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000027_0001
a) step 1: 4-r3-(3-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pwrole-2-carboxyric acid methyl ester
Figure imgf000027_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-Φcarbonyrj-lH-pyrrole-l-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(3-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2-carboxylic acid methyl ester and 3-bromo-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 40% yield as light brown solid (m/e): 389.1 (M+; 100%).
b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(3- bromo-phenyl)-5-methyl-isoxazole-4-carbonyi] - lH-pyrrole-2-carboxylic acid (intermediate 9) was synthesized from 4-[3-(3-bromo-phenyl)-5-methyl-isoxazole-4- carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 93% yield as light-yellow solid.
Intermediate 10 4-[5-Methyl-3-(4-phenoxy-phenyl)-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000028_0001
a) step 1:
4-r5-Methyl-3-(4-phenoxy-phenyl)-isoxazole-4-carbonyll-lH-pwrole-2-carboxyric acid methyl ester
Figure imgf000028_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-Φcarbonyrj-lH-pyrrole-l-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(4-phenoxy -phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2- carboxylic acid methyl ester and 4-phenoxy-N-hydroxybenzenecarboxymidoyl chloride (Journal of Fluorine Chemistry, 111(2), 241-246; 2001) in 88% yield as yellow solid (m/e): 403.0 (M+; 100%).
b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(4- phenoxy-phenyl)-5-methyl-isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid (intermediate 10) was synthesized from 4-[3-(4-phenoxy-phenyl)-5-methyl-isoxazole-4- carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 86% yield as light-yellow solid.
Intermediate 11
4-[3-(4-Benzyloxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000029_0001
a) Step 1:
4-r3-(4-Benzyloxy-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxyric acid methyl ester
Figure imgf000029_0002
According to the procedure described for the synthesis of 4-[3-(4-bromo-phenyl)-5- methyl-isoxazole-Φcarbonyrj-lH-pyrrole-l-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(4-benzyloxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-lH-pyrrole-2- carboxylic acid methyl ester and 4-benzyloxy-N-hydroxybenzenecarboxymidoyl chloride (Journal of Fluorine Chemistry, 111(2), 241-246; 2001) in 90% yield as light yellow solid (m/e): 417.1 (M+; 100%).
b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(4- benzyloxy-phenyl)-5-methyl-isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid (intermediate 11) was synthesized from 4-[3-(4-benzyloxy-phenyl)-5-methyl-isoxazole- 4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 80% yield as light-yellow solid.
Intermediate 12 4-(5-Ethyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid
Figure imgf000030_0001
a) Step 1:
5-Ethyl-3-phenyl-isoxazole-4- carboxylic acid
Figure imgf000030_0002
8.0 g (34 mmol) of 5-Ethyl-3-phenyl-isoxazole-4-carboxylic acid methyl ester (prepared according to: Synthesis 2003; 1347-1356) was dissolved in 50 mLof THF, to which 7.2 g (170 mmol) IiOH H2O in 25 ml of H2O was added in one portion. The reaction mixture was refluxed for 12 h. After evaporation of THF, the aqueous solution was acidified with 2N HCl to pH = 2. After extraction with ethyl acetate (3 x 100 mL), the combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 5-Ethyl-3- phenyl-isoxazole-4- carboxylic acid (6.32 g) in 72.3% yield as a red solid, (m/e): 216.2 (M"; 100%).
b) Step 2:
4-(Ethyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxyric acid methyl ester
Figure imgf000030_0003
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid methyl ester (Example 1, step 1), 4- (ethyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid methyl ester was obtained as light yellow solid in 55% yield, (m/e): 325.2 (M+; 100%). c) Step 3:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[5-ethyl- 3-phenyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 12) was synthesized from 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 75.6% yield as red solid. (m/e):309.3 (M"; 100%).
Intermediate 13
4-[3-(4-Fluoro-phenyl)-5-methoxymethyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid
Figure imgf000031_0001
a) step 1:
5-Methoxymethyl-3-(4-Fluoro-phenyl)-isoxazole-4- carboxylic acid
Figure imgf000031_0002
According to the procedure described for the synthesis of 5-ethyl-3-phenyl-isoxazole-4- carboxylic acid (intermediate 12, step 1), 5-methoxymethyl-3-(4-Fluoro-phenyl)- isoxazole-4- carboxylic acid was synthesised from 5-methoxymethyl-3-(4- Fluorophenyl) -isoxazole-4- carboxylic acid methyl ester (prepared according to: Synthesis 2003; 1347 - 1356) in 72% yield as light yellow solid, (m/e) : 250.2 (M"; 100%) . b) step 2:
Figure imgf000032_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid methyl ester (Example 1, step 1), 4- [3-(4-fluoro-phenyl)-5-methoxymethyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester was obtained in 16% yield as light yellow solid, (m/e): 359.1 (M+; 100%).
c) step 3:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-[3-(4- fluoro-phenyl)-5-methoxymethyl-isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid (intermediate 13) was synthesized from 4-[3-(4-fluoro-phenyl)-5-methoxymethyl- isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 81% yield as red solid, (m/e): 343.2 (M"; 100%).
Intermediate 14 4-(3,5-Diphenyl- isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid
Figure imgf000032_0002
a) step 1:
4-(l-Oxo-4-phenyl-but-2-ynyl)-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000033_0001
According to the procedure described for the synthesis of 4-(l-oxo-but-2-ynyl)-lH- pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 1), 4-(l-oxo-4-phenyl-but-2- ynyl)- lH-pyrrole-2-carboxylic acid methyl ester was synthesized by the reaction of phenyl propynoyl chloride (J. Org. Chem. 68; 2003; 6810 - 6813) with 5-methyl-3- phenyl-isoxazole-4-carboxylic acid (commercially available) in 54% yield as light yellow solid, (m/e): 254.2 (M+; 100%).
b) step 2: 4-(3,5-Diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxyric acid methyl ester
Figure imgf000033_0002
According to the procedure described for the synthesis of 4-(3-(4-bromo-phenyl)-5- methyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-(3,5-diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid methyl ester was obtained from 4-( l-oxo-4-phenyl-but-2-ynyl)- lH-pyrrole-2-carboxylic acid methyl ester and N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 61% yield as white solid, (m/e): 371.4 (M"; 100%).
c) step 3: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1, step 2), 4-(3,5- diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 14) was synthesized from 4-(3,5-diphenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 81% yield as yellow solid.
Intermediate 15 4-[3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]- 1-methyl- lH-pyrrole- 2- carboxylic acid
Figure imgf000034_0001
a) step 1: 4-r3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyll-l-methyl-lH-pyrrole-2- carboxylic acid methyl ester
Figure imgf000034_0002
Amixture of 212 mg (0.5 mmol) 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4- carbonyl]-lH-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 28 mg (0.66 mmol) NaH and 116 mg (0.65 mmol) iodomethane was stirred at room temperature for 24 h. The mixture was then diluted with water and the product extracted with ethyl acetate. The combined organic extracts were then dried with Na2SO4 and evaporated to yield 133 mg (61%) of the title compound as a light yellow solid after purification by chromatography on silica gel eluting with ethyl acetate / heptane, (m/e): 403.3/405.2 (M+H, 100%).
b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(4-bromo- phenyl)-5-methyl-isoxazole-4-carbonyl] - 1-methyl- lH-pyrrole-2-carboxylic acid was synthesised from 4- [3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]- 1-methyl- IH- pyrrole-2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 90% yield as white solid, (m/e): 387.0/389.1 (M-H; 100%).
Example 229
4-(5-Methyl-3-(4-Fluorophenyl)-isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide
Figure imgf000035_0001
a) step 1: 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-2-trichloroacetyl-lH-pyrrole
Figure imgf000035_0002
To a solution of 2.1 g (10 mmol) of 2-trichloroacetyl- lH-pyrrole (commercially available) in CH2Cl2 (35 mL) and nitromethane (17.5 mL), 1.66 g (12.5 mmol) of AlCl3 was added in one portion. Then 2.96 g (12.5 mmol) of 5-methyl-3-(4-fluoro-phenyl)- isoxazole-4-carboxylic acid chloride (example 2, step 1) in 5 mL Of CH2Cl2 was added drop wise. The reaction mixture was stirred at room temperature for 18 h before poured onto ice- water. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The combined organic solution was dried over Na2SO4, and evaporated to dryness. The obtained solid was washed extensively with petroleum ether to give 2.93 g 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-2-trichloroacetyl-lH-pyrrole in 70% yield as yellow solid, (m/e): 414.8 (M+; 100%).
b) step 2:
4-(5-Methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxyric acid (cvclopropylmethyl)-amide
Figure imgf000036_0001
A mixture of 103.8 mg (0.25mmol) 4-(5-methyl-3-(4-fluoro-phenyl)-isoxazole-4- carbonyl)-2-trichloroacetyl-lH-pyrrole, 18 mg (0.25 mmol) cyclpropyl-methylamine, and 25 mg (0.25 mmol) triethylamine was stirred overnight at 60 0C. After cooling to room temperature, the reaction mixture was evaporated to dryness to afford 86.5 mg of the title compound in 94.3% yield as yellow solid, (m/e): 368.1 (M+; 100%).
c) step 3:
To a solution of 121 mg (0.33mmol) 4-(5-methyl-3-(4-phenyl)-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide in dry DMF (2 mL) was added 48.71 mg (0.4mmol) KOt-Bu and the mixture was stirred at room temperature for 30 minutes. The reaction was cooled to 0 C and 70.24 mg (0.50 mmol) methyl iodide was added. The resulting mixture was stirred at room temperature for 8 h. Preparative HPLC (acetonitrile/ water) purification gave 45 mg of 4-(5-methyl-3-(4-fluorophenyl)- isoxazole-4-carbonyl)- l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl) -amide in 35.7% yield as white solid, (m/e): 382.1 (M+; 100%).
Example 230
4-(5-Methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)- l-methyl-pyrrole-2-carboxylic acid (cyclopentyl)-amide
Figure imgf000036_0002
a) Step 1 :
4-(5-Methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxyric acid (cvclopentvD-amide
Figure imgf000037_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide (Example 229, step 2), 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-lH- pyrrole-2-carboxylic acid (cyclopentyl)-amide was synthesized from 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-2-trichloroacetyl- lH-pyrrole and cyclopentylamine (commercially available) in 96% yield as white solid, (m/e): 382.1 (M+; 100%).
b) Step 2
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), 4-(5-methyl-3-(4-fluorophenyl)- isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopentyl)- amide was synthesized from 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)- lH-pyrrole-2- carboxylic acid (cyclopentyl)-amide and methyl iodide in 29% yield as white solid, (m/e): 396.1 (M+; 100%).
According to the procedure described for the synthesis of Example 2 further Aryl- isoxazole-4-carbonyl-pyrrole-2-carboxylic acid amide derivatives have been synthesised from the respective intermediates mentioned in table 1 and the respective amines mentioned in table 1. The compounds are compiled in table 1 and comprise Example 3 to Example 237. Table 1
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
MW
Example ing materials No. Structure Name Start found
[MH+]
4-[3-(4-Fluoro-phenyl)-
4-[3-(4-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
137 lH-pyrrole-2- (intermediate 3) and 354.2
Figure imgf000071_0001
carboxylic acid cyclopropyl- amine cyclopropylamide (commercially available)
4-[3-(4-Fluoro-phenyl)-
4-[3-(4-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
138 lH-pyrrole-2- (intermediate 3) and 368.1 carboxylic acid cyclobutyl-amine
Figure imgf000071_0002
cyclobutylamide (commercially available)
4-[3-(4-Fluoro-phenyl)-
4-[3-(4-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
139 T T lH-pyrrole-2- (intermediate 3) and 3- 408.1 carboxylic acid (3- fluoro-phenyl-amine fluoro-phenyl)-amide (commercially available)
4-[3-(4-Fluoro-phenyl)-
4- [3-(4- Fluoro5-methyl-isoxazole-4- phenyl) -5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] -
140 carboxylic acid lH-pyrrole-2- 358.1 (intermediate 3) and 2-
Figure imgf000071_0003
carboxylic acid (2- hydroxy-ethyl-amine hydroxy-ethyl)-amide (commercially available) MW
Example materials No. Structure Name Starting found
[MH+]
4-[3-(4-Fluoro-phenyl)-
4-[3-(4-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbo-nyl] - lH-pyrrole- isoxazole-4-carbonyl] - 2-carboxylic acid (inter¬
141 lH-pyrrole-2- mediate 3) and 2-(1H- 408.1
Figure imgf000072_0001
carboxylic acid [2-(1H- imidazol-4-yl) -ethyl- imidazol-4-yl) -ethyl] - amine (com-mercially amide available)
4-[3-(4-Fluoro-phenyl)-
4-[3-(4-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbo-nyl] - lH-pyrrole- isoxazole-4-carbonyl] - 2-carboxylic acid
142 lH-pyrrole-2- (intermediate 3) and 405.1 carboxylic acid pyridin-2-ylmethyl-
Figure imgf000072_0002
(pyridin-2-ylmethyl)- amine (commercially amide available)
4-[3-(4-Fluoro-phenyl)-
4- [3-(4- Fluoro5-methyl-isoxazole-4- phenyl) -5-methyl- carbo-nyl] - lH-pyrrole- isoxazole-4-carbonyl] - 2-carboxylic acid
143 lH-pyrrole-2- (intermediate 3) and 2- 427.1 carboxylic acid (2- morpholin-4-yl-ethyl-
Figure imgf000072_0003
morpholin-4-yl-ethyl)- amine (commercially amide available)
4-[3-(4-Fluoro-phenyl)-
4- [3-(4- Fluoro5-methyl-isoxazole-4- phenyl) -5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] -
144 carboxylic acid lH-pyrrole-2- 394.1
Figure imgf000072_0004
(intermediate 3) and carboxylic acid (furan- furan-2-ylmethyl-amine 2-ylmethyl)-amide (commercially available)
Figure imgf000073_0001
MW
Example Struc ing materials No. ture Name Start found
[MH+]
4-[3-(4-Methoxy-
4-[3-(4-Methoxy- phenyl)-5-methyl- phenyl)-5-methyl- isoxazole-4-carbonyl] - isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic
149 lH-pyrrole-2- acid (intermediate 4) 380.2 carboxylic acid and cyclobutyl-amine
Figure imgf000074_0001
cyclobutylamide (commercially available)
4-[3-(4-Methoxy-
4-[3-(4-Methoxy- phenyl)-5-methyl- phenyl)-5-methyl- isoxazole-4-carbonyl] - isoxazole-4-carbonyl] - lH-pyrrole-2-carboxylic
150 lH-pyrrole-2- acid (intermediate 4) 364.1 carboxylic acid prop-2- and prop-2-ynyl-amine
Figure imgf000074_0002
ynylamide (commercially available)
4-[3-(4-Chloro-phenyl)-
4-[3-(4-Chloro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
151 lH-pyrrole-2- (intermediate 5) and 384.0
Figure imgf000074_0003
carboxylic acid cyclobutyl-amine cyclobutylamide (commercially available)
4-[3-(4-Chloro-phenyl)-
4.[3-(4-ChIOrO- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] -
152 carboxylic acid lH-pyrrole-2- 398.1
Figure imgf000074_0004
(intermediate 5) and carboxylic acid cyclopentyl-amine cyclopentylamide (commercially available) MW
Example ng materials No. Structure Name Starti found
[MH+]
4-[3-(4-Chloro-phenyl)-
4-[3-(4-Chloro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
153 lH-pyrrole-2- (intermediate 5) and 2- 374.1
Figure imgf000075_0001
carboxylic acid (2- hydroxy-ethyl-amine hydroxy-ethyl)-amide (commercially available)
4-[3-(4-Chloro-phenyl)-
4-[3-(4-Chloro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
154 lH-pyrrole-2- (intermediate 5) and 370.1 carboxylic acid cyclopropyl- amine
Figure imgf000075_0002
cyclopropylamide (commercially available)
4-[3-(4-Chloro-phenyl)-
4-[3-(4-Chloro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
155 lH-pyrrole-2- (intermediate 5) and 3- 424.1
Figure imgf000075_0003
carboxylic acid (3- fluoro-phenyl-amine fluoro-phenyl)-amide (commercially available)
4-[3-(4-Chloro-phenyl)-
4.[3-(4-ChIOrO- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
156 lH-pyrrole-2- (intermediate 5) and 384.0
Figure imgf000075_0004
carboxylic acid cyclopropylmethyl- cyclopropylmethyl- amine (commercially amide available)
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
MW
Example ing materials No. Structure Name Start found
[MH+]
4-[3-(2-Fluoro-phenyl)-
4-[3-(2-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
173 lH-pyrrole-2- (intermediate 6) and 382.1
Figure imgf000080_0001
carboxylic acid cyclopentyl-amine cyclopentylamide (commercially available)
4-[3-(3-Fluoro-phenyl)-
4-[3-(3-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
174 lH-pyrrole-2- (intermediate 7) and 368.2 carboxylic acid cyclobutyl-amine
Figure imgf000080_0002
cyclobutylamide (commercially available)
4-[3-(3-Fluoro-phenyl)-
4-[3-(3-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
175 lH-pyrrole-2- (intermediate 7) and 2- 358.1
Figure imgf000080_0003
carboxylic acid (2- hydroxy-ethyl-amine hydroxy-ethyl)-amide (commercially available)
4-[3-(3-Fluoro-phenyl)-
4-[3-(3-Fluoro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] -
176 carboxylic acid lH-pyrrole-2- 354.1
Figure imgf000080_0004
(intermediate 7) and carboxylic acid cyclopropyl- amine cyclopropylamide (commercially available)
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
MW
Example ng materials No. Structure Name Starti found
[MH+]
4-[3-(3-Chloro-phenyl)-
4-[3-(3-Chloro- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
193 lH-pyrrole-2- (intermediate 8) and 3- 424.0
Figure imgf000085_0001
carboxylic acid (3- fluoro-phenyl-amine fluoro-phenyl)-amide (commercially available)
4-[3-(3-Bromo-phenyl)-
4-[3-(3-Bromo- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
194 lH-pyrrole-2- (intermediate 9) and 3- 468.0
Figure imgf000085_0002
carboxylic acid (3- fluoro-phenyl-amine fluoro-phenyl)-amide (commercially available)
4-[3-(3-Bromo-phenyl)-
4-[3-(3-Bromo- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
195 lH-pyrrole-2- (intermediate 9) and 442.1 carboxylic acid cyclopentyl-amine
Figure imgf000085_0003
cyclopentylamide (commercially available)
4-[3-(3-Bromo-phenyl)-
4-[3-(3-Bromo- 5-methyl-isoxazole-4- phenyl)-5-methyl- carbonyl] - lH-pyrrole-2- isoxazole-4-carbonyl] - carboxylic acid
196 lH-pyrrole-2- (intermediate 9) and 458.0
Figure imgf000085_0004
carboxylic acid tetrahydro-pyran-4-yl- (tetrahydro-pyran-4- amine (commercially yl)- amide available)
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
In ter mediate 16 4-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000096_0001
a) step 1:
4-r3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000096_0002
According to the procedure described for the synthesis of 4-[3-(4-bromophenyl-5- methyl-isoxazole-4-carbonyl)-lΗ-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-l-Η-pyrrole-2- carboxylic acid methyl ester and 2-chloro-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 55.0% yield as light brown solid, (m/e): 345.1 (M+; 100%). b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid (intermediate 1), 4-[3-(2-chloro- phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 16) was synthesized from 4-[3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole- 2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 98% yield as light-yellow solid, (m/e): 331.1 (M+; 100%).
Example 238
4-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole- 2-carboxylic acid (3-fluoro-phenyl)-amide
Figure imgf000097_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (pyridin-2-ylmethyl)-amide (example 2) the title compound has been synthesized from 4-[3-(2-Chloro-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 16) and 3- fluorophenylamine (commercially available), (m/e): 424.2 (MH+; 100%).
Example 239 4-[3-(3-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylamide
Figure imgf000097_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (pyridin-2-ylmethyl)-amide (example 2) the title compound has been synthesized from 4-[3-(3-bromo-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 9) and cyclopropylamine (commercially available), (m/e): 412.3 (MH+; 100%).
Example 240 4-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide
Figure imgf000098_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (pyridin-2-ylmethyl)-amide (example 2) the title compound has been synthesized from 4-[3-(2-Chloro-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 16) and tetrahydro-pyran-4-ylamine(commercially available), (m/e): 414.7 (MH+; 100%).
Example 241
4-[5-Methyl-3-(4-phenoxy-phenyl)-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclobutylamide
Figure imgf000098_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lΗ-pyrrole-2-carboxylic acid (pyridin-2-ylmethyl)-amide (example 2) the title compound has been synthesized from 4-[5-methyl3-(4-phenoxy- phenyl)-isoxazole-4-carbonyl]-lΗ-pyrrole-2-carboxylic acid (intermediate 10) and cyclobutylamine (commercially available), (m/e): 442.1 (MH+; 100%).
Example 242
4-[5-Methyl-3-(4-phenoxy-phenyl)-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclop en tylamide
Figure imgf000099_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (pyridin-2-ylmethyl)-amide
(example 2) the title compound has been synthesized from 4-[5-methyl3-(4-phenoxy- phenyl)-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (intermediate 10) and cyclopentylamine (commercially available), (m/e): 456.6 (MH+; 100%).
Intermediate 17 4-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
Figure imgf000099_0002
a) step 1:
4-r3-(2-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyll-lH-pyrrole-2-carboxylic acid methyl ester
Figure imgf000099_0003
According to the procedure described for the synthesis of 4-[3-(4-bromophenyl-5- methyl-isoxazole-4-carbonyl)-lΗ-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 4-[3-(2-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid methyl ester was obtained from 4-(l-oxo-but-2-ynyl)-l-Η-pyrrole-2- carboxylic acid methyl ester and 2-bromo-N-hydroxybenzenecarboxymidoyl chloride (commercially available) in 41.3% yield as light brown solid, (m/e): 388.9 (M+; 100%). b) step 2: According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-lH-pyrrole- 2-carboxylic acid (intermediate 1), 4-[3-(2-bromo- phenyl)-5-methyl-isoxazole-4-carbonyi]-lH-pyrrole- 2-carboxylic acid (intermediate 16) was synthesized from 4-[3-(2-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH- pyrrole- 2-carboxylic acid methyl ester through saponification with IiOH H2O. The title compound was obtained in 88.1% yield as light-yellow solid, (m/e): 374.9 (M+; 100%).
Example 243
4-[3-(2-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole- 2-carboxylic acid methyl-prop-2-ynyl-amide
Figure imgf000100_0001
According to the procedure described for the synthesis of 4-(5-Methyl-3-phenyl- isoxazole-4-carbonyl)- lΗ-pyrrole- 2-carboxylic acid (pyridin-2-ylmethyl)-amide (example 2) the title compound has been synthesized from 4-[3-(2-Chloro-phenyl)-5- methyl-isoxazole-4-carbonyl]-lH-pyrrole- 2-carboxylic acid (intermediate 17) and methyl-prop-2-ynylamine (commercially available), (m/e): 426.2 (MH+; 100%).
Example 244
4-[3-(4-Benzyloxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole- 2-carboxylic acid cyclopropylmethyl-amide
Figure imgf000100_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-phenyl- isoxazole-4-carbonyl)- lΗ-pyrrole- 2-carboxylic acid (pyridin-2-ylmethyl)-amide (example 2) the title compound has been synthesized from 4-[3-(4-benzyl oxy-phenyl)- S-methyl-isoxazole-ΦcarbonylJ-lH-pyrrole-l-carboxylic acid (intermediate 11) and cyclopropylmethylamine (commercially available), (m/e): 442.2 (MH+; 100%).
Intermediate 18
4-[3-(3,4,5-trifluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH- pyrrole
Figure imgf000101_0001
a) step 1:
5-Methyl r3-(3A5-fluroro -phenyl) -isoxazole-4-carboxylic acid
Figure imgf000101_0002
According to the procedure described for the synthesis of 5-ethyl-3-phenyl-isoxazole-4- carboxylic acid (intermediate 12, step 1), 5-Methyl [3-(3,4,5-fluroro -phenyl) -isoxazo Ie- 4-carboxylic acid was synthesized from 5-Methyl [3-(3,4,5-fluroro -phenyl) -isoxazo le-4- carboxylic acid ethyl ester (prepared according to: Synthesis 2003; 1347 - 1356) in 53.7% yield as light yellow solid, (m/e): 258.5 (M+ 1; 100%). b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophen yl) -isoxazo le-4-carbonyl) -2- trichloroacetyl- lH-pyrrole (example 229, step 1),
4-[3-(3,4,5-trifluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH- pyrrole (intermediate 18) was synthesized from 5-methyl [3-(3,4,5-fluroro -phenyl)- isoxazole-4-carboxylic acid in 47.1% yield as light-yellow solid, (m/e): 452.3 (M+ 1;
100%).
Example 245 4-[5-Methyl-3-(3,4,5-trifluoro-phenyl)-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclop en tylamide
Figure imgf000102_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-lΗ-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4,5- trifluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH-pyrrole
(intermediate 18) and cyclopentylamine (commercially available) in 49.6 yield, (m/e):
418.3 (MH+; 100%).
Example 246 l-Methyl-4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclopropylmethyl-amide
Figure imgf000102_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), 4-(5-methyl-3-phenyl-isoxazole-4- carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide was synthesized from 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lΗ-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 12) in 31.7% yield as white solid, (m/e): 364.6 (M+ 1; 100%).
Example 247 l-Methyl-4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclop en tylamide
Figure imgf000103_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), 4-(5-methyl-3-phenyl-isoxazole-4- carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopentyl)-amide was synthesized from 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lΗ-pyrrole-2-carboxylic acid (cyclopentyl)- amide in 38.7% yield as white solid, (m/e): 378.3 (M+ 1; 100%).
Example 248
4-[5-methyl-3-(3-Fluoro-phenyl)-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid cyclopropylmethyl-amide
Figure imgf000103_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), 4-[5-methyl-3-(3-fluorophenyl)- isoxazole-4-carbonyl)- l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide was synthesized from 4-[5-methyl-3-(3-flurophenyl)-isoxazole-4-carbonyl] - lΗ-pyrrole- 2-carboxylic acid (cyclopropylmethyl)-amide in 27% yield as white solid, (m/e): 382.3 (M+ 1; 100%).
Example 249 4-[3-(3-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid prop-2-ynylamide
Figure imgf000104_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl) -isoxazole-4-carbonyl)- l-methyl-pyrrole-2-carboxylic acid
(cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-lΗ-pyrrole-2-carboxylic acid prop-2-ynylamide (example 179) in 43% yield as white solid, (m/e): 366.1 (M+ 1;
100%).
Example 250
4-[3-(3-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid cyclop en tylamide
Figure imgf000104_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl) -isoxazole-4-carbonyl)- l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-lΗ-pyrrole-2-carboxylic acid cyclopen tylamide (example 178) in 27.6% yield as white solid, (m/e): 396.2 (M+ 1; 100%).
Example 251 4-[3-(3-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid cyclobutylamide
Figure imgf000105_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-l-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-lΗ-pyrrole-2-carboxylic acid cyclobutylamide (example 174) in 34.2% yield as white solid, (m/e): 382.1 (M+ 1; 100%).
Intermediate 19
4-[3-(3,4 -difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH- pyrrole
Figure imgf000105_0002
a) step 1:
5-Ethyl-3-(3,4-dipheny)l-isoxazole-4- carboxylic acid
Figure imgf000105_0003
According to the procedure described for the synthesis of 5-ethyl-3-phenyl-isoxazole-4- carboxylic acid (intermediate 12, step 1), 5-methyl-3-(3,4-difluoropheny)l-isoxazole-4- carboxylic acid was synthesized from 5-methyl-3-(3,4-difluorophenyl)-isoxazole-4- carboxylic acid ethyl ester (prepared according to: Synthesis 2003; 1347 - 1356) in 25% yield as yellow solid, (m/e) : 240.1 (M+ 1 ; 100%) .
b) step 2:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)-2-trichloroacetyl-lH-pyrrole (example 229, step 1), 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH-pyrrole (intermediate 18) was synthesized from 5-methyl [3-(3,4-diflurorophenyl)-isoxazole-4- carboxylic acid in 46.0% yield as yellow solid, (m/e): 433.0 (M+ 1; 100%).
Example 252 4-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylmethyl-amide
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)- lΗ-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4- difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH-pyrrole (intermediate 19) and cyclopropylmethylamine (commercially available) in 35.8 yield, (m/e): 386.1 (MH+; 100%).
Example 253
4-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid prop-2-ynylamide
Figure imgf000107_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4- difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl] -2-trichloroacetyl- lH-pyrrole
(intermediate 19) and prop-2-ynylamine (commercially available) in 28.1 yield, (m/e): 370.0 (MH+; 100%).
Example 254 4-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide
Figure imgf000107_0002
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)- lΗ-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4- difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl] -2-trichloroacetyl- lΗ-pyrrole (intermediate 19) and tetrahydro-pyran-4-yl amine(commercially available) in 41.5 yield, (m/e): 416.1 (MH+; 100%).
Example 255
4-[3-(3,4-Difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclop en tylamide
Figure imgf000108_0001
According to the procedure described for the synthesis of 4-(5-methyl-3-(4- fluorophenyl)-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (cyclopropylmethyl)- amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4- difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-lH-pyrrole (intermediate 19) and cyclopentylamine (commercially available) in 38.1 yield, (m/e): 400.1 (MH+; 100%).

Claims

Claims
1. Aryl-isoxazole-4-carbonyl-pyrrole-2-carboxylic acid amide derivatives of formula
Figure imgf000109_0001
wherein
R1 is hydrogen, halogen, lower alkoxy, phenyloxy or benzyloxy;
R2 is lower alkyl, (CH2)n-O-lower alkyl or phenyl;
R3 is hydrogen or lower alkyl; R4/R5 are independently from each other hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkynyl or -(CHR)n-aryl, unsubstituted or substituted by halogen, lower alkyl or lower alkoxy, -(CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two lower alkyl groups, -(CH2)n-aromatic heterocyclic rings,
-(CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl, -(CHR)n-O-lower alkyl, -(CRz)n-OH, -(CHR)n-NR5R", or R4/R5 form together with the N-atom to which they are attached the ring
- 8-aza-bicyclo[3.2.1] octane, substituted by hydroxy, or
- 3,4-dihydro- lH-isoquinoline, or
- a non aromatic heterocyclic ring, unsubstituted or substituted by one or two substituents, selected from the group consisting of C(O)O-lower alkyl, lower alkyl, lower alkyl substituted by halogen, cycloalkyl, hydroxy, halogen, N(R)C(O)-lower alkyl, -(CΗ2)n-O-lower alkyl, or by an aromatic heterocyclic ring; R is hydrogen, hydroxy, or lower alkyl, wherein R may be the same or different in case of R2;
RVR" are independently from each other hydrogen or lower alkyl; n is 0, 1, 2, 3 or 4; m is 1, 2 or 3;
and their pharmaceutically acceptable acid addition salts.
2. Compounds of formula I according to claim 1, in which R1 is hydrogen or halogen, R2 is methyl, ethyl or CH2OCH3, R3 is hydrogen or methyl and R4 and R5 do not form together with the N atom a heterocyclic ring.
3. Compounds of formula I according to claim 1, in which R1 is hydrogen or halogen, R2 is methyl, ethyl or CH2OCH3, R3 is hydrogen or methyl and R4 and R5 form together with the N atom a heterocyclic ring.
4. Compounds of formula I according to claim 2, wherein R1 is hydrogen, R2 is methyl or ethyl, R3 and R4 are hydrogen and R5 is (CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl.
5. Compounds of formula I according to claim 4, which compounds are 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide, 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid cyclobutylamide,
4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclopentylamide,
4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide or
4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)-lH-pyrrole-2-carboxylic acid cyclopropylamide.
6. Compounds of formula I according to claim 2, wherein R1 is hydrogen, R2 is methyl or ethyl, R3 and R4 are hydrogen and R5 is (CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two lower alkyl groups.
7. Compounds of formula I according to claim 6, wherein the ompounds are 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (tetrahydro- pyran-4-yl)-amide or
4-(5-ethyl-3-phenyl-isoxazole-4-carbonyl)- lH-pyrrole-2-carboxylic acid (tetrahydro- pyran-4-yl)-amide.
8. Compounds of formula I according to claim 2, wherein R1 is Br, R2 is methyl, R 3 is methyl, R4 is hydrogen and R5 is (CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two lower alkyl groups.
9. Compounds of formula I according to claim 8, which compounds are 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid (tetrahydro-pyran-4-yl)-amide or
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-l-methyl-lH-pyrrole-2- carboxylic acid (3-morpholin-4-yl-propyl)-amide.
10. Compounds of formula I according to claim 2, wherein R1 is Br, Cl or F, R2 is methyl or CH2OCH3 , R3 and R4 are hydrogen and R5 is (CH2)n-non aromatic heterocyclic ring, unsubstituted or substituted by one or two lower alkyl groups.
11. Compounds of formula I according to claim 10, which compounds are
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide,
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (2,2-dimethyl-tetrahydro-pyran-4-yl)-amide,
4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide, 4-[3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid
(tetrahydro-pyran-4-yl)-amide,
4-[3-(4-fluoro-phenyl)-5-methoxymethyl-isoxazole-4-carbonyl]-lH-pyrrole-2- carboxylic acid (tetrahydro-pyran-4-yl)-amide or
4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide. - Ill -
12. Compounds of formula I according to claim 2, wherein R1 is Br, Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is lower alkyl or alkynyl.
13. Compounds of formula I according to claim 12, which compounds are 4-[3-(4-Bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid isopropylamide,
4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid prop-2-ynylamide or
4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid prop-2-ynylamide.
14. Compounds of formula I according to claim 2, wherein R1 is Br, Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is (CR2)n-cycloalkyl, unsubstituted or substituted by one to three substituents, selected from the group consisting of hydroxy or lower alkyl.
15. Compounds of formula I according to claim 14, which compounds are
4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid (4-hydroxy-cyclohexyl)-amide,
4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide,
4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylamide, 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclobutylamide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylamide,
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopropylmethyl- amide,
4-[3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide, 4-[3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide or
4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-lH-pyrrole-2-carboxylic acid cyclopentylamide.
16. Compounds of formula I according to claim 2, wherein R1 is Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is (CR2)n-OH.
17. Compounds of formula I according to claim 16, which compounds are 4-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]- lH-pyrrole-2-carboxylic acid (2- hydroxy-ethyl)-amide or
4-[3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]- lH-pyrrole-2-carboxylic acid (2-hydroxy-ethyl)-amide.
18. Compounds of formula I according to claim 2, wherein R1 is Cl or F, R2 is methyl, R3 and R4 are hydrogen and R5 is (CH2)n-aromatic heterocyclic ring.
19. Compounds of formula I according to claim 18, which compounds are 4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]- lH-pyrrole-2-carboxylic acid [2-( lH-imidazol-4-yl)-ethyl] -amide, 4-[3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]- lH-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide,
4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]- lH-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide or
4-[3-(4-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]- lH-pyrrole-2-carboxylic acid [2-( lH-imidazol-4-yl)-ethyl] -amide.
20. A process for preparation of compounds of formula I as defined in claim 1, which process comprises
a) reacting a compound of formula
Figure imgf000113_0001
with an amine of formula Ff
HN
V III in the presence of TBTU and N,N-diisopropylethylamine
to a compound of formula
Figure imgf000114_0001
wherein R1, R2, R3, R4 and R5 and m are as described above, or b) reacting a compound of formula
Figure imgf000114_0002
with an amine of formula
Ff
HN
V III to a compound of formula
Figure imgf000114_0003
wherein R1, R2, R4 and R5 and m are as described above, c) reacting a compound of formula
Figure imgf000115_0001
with an alkyliodide of formula R3I (for R3 = lower alkyl) to a compound of formula
Figure imgf000115_0002
wherein R1, R2, R4 and R5 and m are as described above and R3 is lower alkyl, and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
21. A compound of formula I according to claim 1, whenever prepared by a process as claimed in claim 20 or by an equivalent method.
22. A medicament containing one or more compounds of formula I in accordance with claim 1 and pharmaceutically acceptable excipients.
23. A medicament according to claim 22 for the treatment of diseases related to the
GABA A cc5 subunit selected from cognitive enhancer or cognitive disorders.
24. A medicament according to claim 23 for the treatment of Alzheimer's disease.
25. The use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of cognitive enhancer or cognitive disorders.
26. The use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of Alzheimer's disease.
27. The invention as hereinbefore described.
***
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