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WO2010059922A1 - Composés de pyrrolidine carboxamide - Google Patents

Composés de pyrrolidine carboxamide Download PDF

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Publication number
WO2010059922A1
WO2010059922A1 PCT/US2009/065290 US2009065290W WO2010059922A1 WO 2010059922 A1 WO2010059922 A1 WO 2010059922A1 US 2009065290 W US2009065290 W US 2009065290W WO 2010059922 A1 WO2010059922 A1 WO 2010059922A1
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Prior art keywords
carboxamide
pyrrolidine
ethyl
trifluoromethyl
phenyl
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Andrew G. Cole
Jeffrey John Letourneau
Koc-Kan Ho
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Ligand Pharmaceuticals Inc
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Ligand Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pyrrolidine carboxamide compounds, which may be useful for the treatment and prevention of pain and inflammatory disorders.
  • Somatostatins which are also known as somatotropin release inhibiting factors (SRIFs)
  • SRIFs somatotropin release inhibiting factors
  • Somatostatins exert their effects through five SRIF receptors (SSt 1 , SSt 2 , SSt 3 , sst 4 and SSt 5 ).
  • GPCRs G-protein coupled receptors
  • SRIF- 14 and SRIF-28 which contain 14 and 28 amino acids respectively, are two key members of the somatostatin peptide family. They bind to these five receptors with nanomolar affinity (Weckbecker et al, Nature Reviews Drug Discovery, 2003, 2, 999-1017; Pinter et al, Pharmacology & Therapeutics, 2006, 112, 440-456).
  • J-2156 alleviates pain and inflammatory responses in the mouse formalin paw test (FPT), rat sciatic nerve ligation model and rat Complete Freund's adjuvant (CFA) model
  • FPT formalin paw test
  • CFA Complete Freund's adjuvant
  • sst4 agonists could be useful to treat airway inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Heptapeptide TT-232 is a tyrosine kinase inhibitor that also shows high affinity to sstl, sst2, sst3 and sst4 subtypes (Simon et al, J. of MoI. Structure: THEOCHEM, 2007, 816, 73-76).
  • TT-232 is currently in clinical trials for cancer and its anti-inflammatory and anti-nociceptive activity was related to the agonistic activity of the sst4 subtype (Keri et al, Int. J. of Peptide Res. and Ther. 2005, 11, 3-15).
  • the antiinflammatory and neurogenic inflammatory inhibitory activity in combination with antiproliferative activity may contribute to the favorable profile for TT-232 as an anti-cancer agent, and in turn suggests that a small sst4 agonist can be potentially useful as a combination therapy for cancer.
  • sst4 agonist may be useful for treatment of glaucoma.
  • a thiourea compound NNC 26-9100 was published for such potential utility (Liu et al, J. Med. Chem., 1998, 41, 4693-4705).
  • the present invention relates to pyrrolidine carboxamide compounds.
  • such compounds can include sst4 agonists.
  • such compounds can be useful for the treatment and prevention of pain and inflammatory disorders.
  • Some embodiments include compounds or salts thereof of formula:
  • R 1 and R 2 are each independently selected from hydrogen and (Ci-C 6 ) alkyl or together, R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl;
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl
  • R 4 is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R 4 is not para-cyanophenyl;
  • R 5 is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R 5 is not para-methoxyphenyl or para- chlorophenyl, and that when R 5 is pyridinyl or pyrimidinyl, R 1 must be (Ci-C 6 ) alkyl.
  • R 1 and R 2 are each independently selected from hydrogen and (Ci-C 6 ) alkyl, or together R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl;
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl;
  • R 4 is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R is not para-cyanophenyl;
  • R 5 is chosen from optionally substituted heterocyclyl and optionally substituted aryl
  • Y is a direct bond or -CH 2 or together, Y and R 1 can form a cyclopropane;
  • R 5 when R 5 is pyridinyl or pyrimidinyl, R 1 must be (Ci-C 6 ) alkyl and that when Y is a direct bond, R 5 is not para-methoxy phenyl or para- chlorophenyl.
  • R 8 is selected from hydrogen, trifluoromethyl, chloro, fluoro, (Ci-C 6 ) alkyl, (Ci-C 6 ) alkyoxy and trifluoromethoxy;
  • R 9 and R 10 are each independently chosen from hydrogen, halogen, (C]-C 6 ) alkyl, trifluoromethyl, (Ci-C 6 ) alkoxy, trifluoromethoxy and cyano; or
  • R 8 and R 9 together, or R 9 and R 10 together, along with the phenyl to which they are attached, can form napthyl;
  • R 1 1 and R 12 are each independently hydrogen, fluoro, chloro, methoxy or (Ci-C 6 ) alkyl;
  • R 13 is hydrogen, fluoro or methyl
  • R 11 and R 12 together, or R 12 and R 13 together, along with the phenyl to which they are attached, can form napthyl.
  • Some embodiments include mixtures of stereoisomers or salts thereof falling within the genus described by formula I:
  • R 1 and R 2 are each independently selected from hydrogen and (Ci-C 6 ) alkyl or together, R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl;
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl
  • R 4 is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R 4 is notp ⁇ ra-cyanophenyl;
  • R 5 is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R 3 is not /? ⁇ r ⁇ -methoxy phenyl or para- chlorophenyl, and that when R 5 is pyridinyl or pyrimidinyl, R 1 must be (Ci-C 6 ) alkyl; and
  • At least 51% of said mixture contains the 3 S configuration of the pyrrolidine.
  • Some embodiments include mixtures and salts thereof falling within the genus described by formula:
  • R 1 and R 2 are each independently selected from hydrogen and (C]-C 6 ) alkyl or together, R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl; [0041] R 3 is selected from hydrogen and (Ci-C 6 ) alkyl;
  • R 4 is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R 4 is notp ⁇ ra-cyanophenyl;
  • R 3 is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R 5 is not /? ⁇ r ⁇ -methoxyphenyl or para- chlorophenyl, and that when R 5 is pyridinyl or pyrimidinyl, R 1 must be (Ci-C 6 ) alkyl.
  • R is selected from hydrogen, trifluoromethyl, chloro, fluoro, (Cj-C 6 ) alkyl, (Ci-C 6 ) alkyoxy and trifluoromethoxy;
  • R and R 10 are each independently chosen from hydrogen, halogen, (C]-C 6 ) alkyl, trifluoromethyl, (Ci-C 6 ) alkoxy, trifluoromethoxy and cyano; or
  • R 8 and R 9 together, or R 9 and R 10 together, along with the phenyl to which they are attached, can form napthyl;
  • R 1 1 and R 12 are each independently hydrogen, fluoro, chloro, methoxy or (Ci-C 6 ) alkyl;
  • R 13 is hydrogen, fluoro or methyl
  • R 1 ' and R 12 together, or R 12 and R 13 together, along with the phenyl to which they are attached, can form napthyl.
  • Some embodiments include compounds or salts thereof of formula:
  • R 1 and R 2 are each independently selected from hydrogen and (C i -C 6 ) alkyl, or together R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl;
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl
  • R 4 is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R 4 is not/? ⁇ ra-cyanophenyl;
  • R 5 is chosen from optionally substituted heterocyclyl and optionally substituted aryl
  • Y is a direct bond or -CH 2 or together, Y and R 1 can form a cyclopropane;
  • R 5 when R 5 is pyridinyl or pyrimidinyl, R 1 must be (Ci-C 6 ) alkyl and that when Y is a direct bond, R 5 is not /? ⁇ r ⁇ -methoxyphenyl or par a- chlorophenyl.
  • R is hydrogen, trifluoromethyl, chloro, fluoro, (C]-C 6 ) alkyl, (Ci-C 6 ) alkyloxy or trifluoromethoxy;
  • R 9 and R 10 are each independently chosen from hydrogen, halogen, (Ci-C 6 ) alkyl, trifluoromethyl, (C)-C 6 ) alkoxy, trifluoromethoxy and cyano; or
  • R 8 and R 9 together, or R 9 and R 10 together, along with the phenyl to which they are attached, can form napthyl;
  • R 1 1 and R 12 are each independently hydrogen, fluoro, chloro, methoxy or (C 1 -C 6 ) alkyl;
  • R 13 is hydrogen, fluoro or methyl
  • R 1 1 and R 12 together, or R 12 and R 13 together, along with the phenyl to which they are attached, can form napthyl.
  • Some embodiments include a foregoing compound, mixture or salt thereof, and a pharmaceutically acceptable carrier.
  • some embodiments include methods of treating disorders dependent on the modulation of sst4. Some such methods include administering a foregoing compound, mixture or salt thereof to a patient in need thereof.
  • Some embodiments include the use of a foregoing compound, mixture or salt thereof in the preparation of a medicament for treating a disorder dependent on the modulation of sst4.
  • disorders modulated by sst4 include types of pain, inflammatory conditions, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injuries, and psychiatric disorders.
  • Figure IA shows an Oak Ridge Thermal Ellipsoid Program (ORTEP) plot for the crystal structure of compound 11a.
  • Figure IB shows an embodiment of the structure of compound 11a.
  • the present invention relates to certain pyrrolidine carboxamide agonists of sst 4 , which may be useful for the treatment and prevention of pain and inflammatory disorders.
  • a compound of formula I, or salt thereof is provided, wherein formula I is:
  • R ! and R 2 are each independently selected from hydrogen and (Ci-C 6 ) alkyl or together, R 1 and R 2 may form a (C 3 -C 6 ) cycloalkyl.
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl.
  • R 4 and R 5 are each selected from optionally substituted heterocyclyl and optionally substituted aryl.
  • a mixture of formula I is provided. In some embodiments, a mixture of stereoisomers of formula I is provided. In some embodiments, at least 51% of a mixture can contain the 3S configuration of the pyrrolidine.
  • a mixture can include a racemic mixture comprising compounds of formula Ib, or salt thereof, wherein formula Ib is:
  • R 1 and R z are each independently selected from hydrogen and (C]-C 6 ) alkyl or together, R 1 and R 2 may form a (C 3 -C 6 ) cycloalkyl; R 3 is selected from hydrogen and (Cj-C 6 ) alkyl; R 4 and R 5 are each selected from optionally substituted heterocyclyl and optionally substituted aryl; Y is a direct bond or -CH 2 or together, Y and R 1 may form a cyclopropane.
  • R 5 when R 5 is pyridinyl or pyrimidinyl, R 1 must be (Ci-C 6 ) alkyl and that when Y is a direct bond, R 5 is not /? ⁇ ra-methoxyphenyl or para- chlorophenyl.
  • the configuration of the pyrrolidine ring is 3S. In some embodiments, the configuration is 4R. It will be understood that in some instances, for example, in a compound where R 4 is a heterocyclyl with the heteroatom at the 2- position, while the absolute configuration of the substituents is the same as in the others, the nomenclature may change to 4S.
  • compositions comprising a pharmaceutically acceptable carrier and a compound and/or mixture of formula I, formula Ib, formula II, or salt thereof.
  • Some embodiments include methods of treating or preventing disorders dependent upon the modulation of sst 4 . Some methods include administering compounds, mixtures and/or pharmaceutical compositions provided herein to a subject (e.g. human) in need thereof.
  • a subject e.g. human
  • the present invention provides a method of treatment comprising administering a therapeutically effective amount of a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention to a subject (e.g. human) in need of such treatment.
  • Some embodiments include methods of treating neurological discorders such as pain, Alzheimer's disease, temporal lobe epilepsy, Parkinson's, cortical injury, psychiatric disorders, and inflammatory conditions, the method comprising administering a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention to a subject in need of such treatment.
  • neurological discorders such as pain, Alzheimer's disease, temporal lobe epilepsy, Parkinson's, cortical injury, psychiatric disorders, and inflammatory conditions
  • Some embodiments include a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention for use in therapy. Some embodiments include a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in therapy.
  • Some embodiments include the use of a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention for use in the manufacture of a medicament for the treatment of neurological indications, psychiatric disorders and inflammatory conditions. Some embodiments include the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neurological indications, psychiatric disorders and inflammatory conditions.
  • a particular disorder is pain such as inflammatory pain.
  • a further disorder is Alzheimer's disease. Examples of pain that may be treated with compounds provided herein include nociception.
  • pain that may be treated with compounds provided herein conditions include osteoarthritis, acute gout, inflammatory arthropathy, dysmenorrhoea, endometriosis, headache, migraine, postoperative pain, back pain, sciatica, sprains, strains, rheumatism, dental pain, kidney stones and fever.
  • inflammatory confditions that can be treated with compounds provided herein include airway inflammatory conditions.
  • airway inflammatory conditions include asthma, chronic obstructive pulmonary disesase
  • Alkyl (whether alone or as part of another group) includes linear, branched, or cyclic hydrocarbon structures and combinations thereof.
  • a combination can be, for example, cyclopropylmethyl.
  • the term can refer to alkyl of 10 or fewer carbons.
  • Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like.
  • Preferred alkyl and alkylene groups are those of Ci 0 or below (e.g. Ci, C 2 , C 3 , C 4 , C 5 .
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms.
  • Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • Representative alkyl groups include linear or branched Ci to C 6 alkyl, such as Ci to C 3 alkyl, for example methyl or ethyl.
  • Representative cycloalkyl groups include C 3 to C 6 cycloalkyl, such as c-propyl, c-butyl, c-pentyl, c-hexyl.
  • Ci to C 20 Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • carbocycle includes ring systems in which the ring atoms are all carbon atoms of any oxidation state.
  • carbocycle refers to such systems as cyclopropane, benzene and cyclohexene;
  • C 8 - C] 2 carbopoly cycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a linear, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. Alkoxy and lower alkoxy can include methylenedioxy and ethylenedioxy. Representative alkoxy or alkoxyl groups include methoxy and ethoxy.
  • Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched or cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, propionyl, isobutyryl, /-butoxy carbonyl, benzoyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • the double bonded oxygen when referred to as a substituent itself, is called "oxo".
  • Aryl and heteroaryl refers to (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14- membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
  • the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • aryl can refer to residues in which one or more rings are aromatic, but not all need be.
  • Representative aryl groups include phenyl and naphthyl, such as phenyl.
  • Representative heteroaryl groups include a 5- or -6 membered heteroaromatic ring containing 1-4 (such as 1 or 2, e.g. 1) heteroatoms selected from O, N, or S. Examples of heteroaryl groups include pyridinyl, thiophenyl and furanyl. Particular examples are thiophenyl and furanyl.
  • Arylalkyl refers to an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like. This is in contradistinction to alkylaryl, in which an aryl residue is attached to the parent structure through alkyl (e.g. a p-tolyl residue).
  • Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons.
  • heterocycle refers to a monocyclic, bicyclic or tricyclic residue with 1 to 13 carbon atoms and 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle may be non-aromatic or aromatic.
  • the heterocycle may be fused to an aromatic hydrocarbon radical.
  • Examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triaziny
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms. Examples include piperidine, piperazine, morpholine, pyrrolidine and thiomorpholine. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic; examples include pyridine, pyrrole and thiazole.
  • heterocyclyl residues additionally include piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, A- piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamo ⁇ holinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone,
  • substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms (for example, 1 or 2) in each residue are replaced with a specified radical.
  • Haloakyl refers to an alkyl group in which one or more hydrogens are replaced by halogen, for example, trifluoromethyl, trifluoromethoxy, trichloroethyl. and difluoromethyl.
  • 'Oxo is also included among the substituents referred to in "'optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
  • 1, 2 or 3 hydrogen atoms are replaced with a specified radical.
  • 1 or 2 hydrogen atoms are replaced with a specified radical.
  • alkyl, aryl, heterocyclyl, etc may be substituted by 1 or 2 substituents selected from the group consisting Of CpC 4 alkyl (e.g. methyl), Ci-C 4 alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl, trifluoromethoxy.
  • substituents selected from the group consisting Of CpC 4 alkyl (e.g. methyl), Ci-C 4 alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl, trifluoromethoxy.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
  • the term oxaalkyl is intended as it is understood in the art, namely, it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds) (Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1196, but without the restriction of ⁇ fI 27(a), incorporated by reference in its entirety). It does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • halogen refers to fluorine, chlorine, bromine or iodine. Representative examples of halogen are fluorine and chlorine.
  • haloalkyl and “haloalkoxy” refers to alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
  • the compounds provided herein can include radiolabeled compounds, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • radioisotopes of hydrogen, carbon, phosphorous, sulfur, and fluorine include 3 H, 14 C, 32 P, 35 S, and 18 F, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are envisaged. Tritiated ( 3 H) and carbon- 14 ( 14 C) radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • the term "methods of treating or preventing” can refer to amelioration, prevention or relief from the symptoms and/or effects associated with disorders.
  • the term “preventing” as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition, to diminish the likelihood or severity of the condition. It will be understood that the term “prevent” is not an absolute term, and can refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition.
  • treatment of a patient is intended to include prophylaxis.
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • any carbon-carbon double bond appearing herein may be illustrative of particular embodiments, and may not be intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion.
  • [0102] can indicate a 50:50 mixture of the following trans enantiomers:
  • diastereomers are named and data is provided; however, it is to be understood that it may not be known which chemical name matches the structural representation.
  • S-, S-, R- (or, in the case of R 4 as a heteroaryl or another substituent that would change the orientation around position 4, S-, S-, S-) configuration may have increased activity, an example includes:
  • An individual isomer or diastereoisomer isolated such as to be substantially free of the other isomer or diastereoisomer (i.e. pure) may be isolated such that less than about 10%, particularly less than about 1%, for example less than about 0.1% of the other isomer or diastereoisomer is present.
  • the compounds described herein may be in a crystalline or amorphous state. Furthermore, if crystalline, the compounds may exist in one or more polymorphic forms. The most thermodynamically stable polymorphic form, at room temperature, of compounds of formula (I), (Ib) and (II) are of particular interest.
  • Polymorphic forms of compounds may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid state nuclear magnetic resonance
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifiuoromethanesulfonyl, toluenesulfonyl and methanesulfonyl, respectively.
  • a comprehensive list of abbreviations appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations,” is incorporated herein by reference in its entirety.
  • compositions and compounds of the invention While it may be possible for the mixtures and compounds of the invention to be administered as the raw chemical, it is possible to present them as a pharmaceutical composition.
  • a pharmaceutical composition comprising formula I, formula Ib, formula II, pharmaceutically acceptable salts, and/or mixtures thereof, and one or more pharmaceutically acceptable carriers thereof are provided.
  • compositions may further comprise one or more additional therapeutic ingredients.
  • the carrier(s) can be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions are provided suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Some methods include the step of bringing into association an active ingredient, for example, formula I, formula Ib, formula II, pharmaceutically acceptable salts, solvates and/or mixtures thereof, and a pharmaceutically acceptable carrier, which may constitute one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association an active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired compositions.
  • compositions provided herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of an active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • compositions may include a "pharmaceutically acceptable inert carrier.”
  • a pharmaceutically acceptable inert carrier can include one or more inert excipients, for example, starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or non-aqueous techniques. Pharmaceutically acceptable carriers may also include controlled release means well known in the art.
  • compositions and formulations provided herein may optionally include additional ingredients for example, therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient can be compatible with compounds provided herein to insure the stability of the formulation.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient can be determined by an attendant physician. However, the dose employed will depend on a number of factors, including, for example, the age, sex, and weight of the patient, the precise disorder to be treated, and the severity of the disorder.
  • a compound can include salts, solvates and inclusion complexes of that compound.
  • a compound of formula II as depicted above would include salts in which -NR 3 is NH + M " , wherein M is any suitable counterion.
  • some structures depicted herein can include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the structures provided herein except, for example, for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C- enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • solvate can refer to formula I, formula Ib, formula II, and/or mixtures thereof in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19 th Ed. (1995) volume 1 , page 176-177, which is incorporated herein by reference in its entirety. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, pamoic, pantothenic, phosphoric, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Compounds provided herein of formula I, formula Ib, formula II, and/or mixtures thereof are modulators of sst 4 .
  • Such compounds have utility in treating and preventing pain and inflammatory conditions, as well as other disorders such as, but not necessarily limited to, Alzheimer's disease and psychiatric disorders.
  • pain that may be treated with compounds provided herein include nociception. More examples of pain that may be treated with compounds provided herein conditions include osteoarthritis, acute gout, inflammatory arthropathy, dysmenorrhoea, endometriosis, headache, migraine, postoperative pain, back pain, sciatica, sprains, strains, rheumatism, dental pain, kidney stones and fever.
  • Examples of inflammatory confditions that can be treated with compounds provided herein include airway inflammatory conditions. Examples of airway inflammatory conditions include asthma, chronic obstructive pulmonary disesase
  • Pyrrolidine carboxamides provided herein are agonists for the sst 4 receptor.
  • Somatostatins SRIF- 14 and SRIF-28 which contain 14 and 28 amino acids respectively, are two key members of the somatostatin peptide family and bind to the five somatostatin (sst) receptors with nanomolar affinity (Weckbecker et al, Nature Reviews Drug Discovery, 2003, 2, 999-1017; Pinter et al, Pharmacology & Therapeutics, 2006, 112, 440-456, incorporated by reference in its entirety).
  • SSt 4 sub-type selective small molecule agonist will be a useful therapeutic agent for treatment of various pain and inflammatory conditions.
  • a selective modulator will prevent or minimize the potential endocrine side effects mediated through other receptor sub-types.
  • One aspect of the invention relates to a mixture of isomers or a mixture of compounds wherein at least 51 % of said mixture contains the 3S configuration of the pyrrolidine, falling within the genus described by formula I:
  • Another aspect of the invention relates to a racemic mixture of the isomers of formula Ib: Ib.
  • R 1 and R 2 are each independently selected from hydrogen and (Ci-C 6 ) alkyl or together, R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl;
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl;
  • R 4 and R 5 are each selected from optionally substituted heterocyclyl and optionally substituted aryl;
  • R 4 and R 5 are each selected from heterocyclyl and aryl each optionally substituted with one or more of hydrogen, trifluoromethyl, halogen, (C]-C 6 ) alkyl, (Ci-C 6 ) alkyoxy, cyano and trifluoromethoxy.
  • Certain substituents in certain positions of the R 4 and R 5 aryls and heteroaryls may lead to a decrease in activity.
  • R 3 is hydrogen and R 4 and R 5 are each selected from optionally substituted phenyl.
  • R 4 is a phenyl substituted with one or more of hydrogen, fluorine or methoxy.
  • R 5 is a phenyl substituted with one or more of hydrogen, trifluoromethyl, chlorine, methoxy or fluorine.
  • R 4 is optionally substituted naphthyl or thiophene.
  • R 5 is optionally substituted naphthyl, pyrindinyl or indolyl.
  • R 1 is methyl or ethyl and R 2 is hydrogen, and the R 1 -bearing carbon is in the S configuration.
  • R 1 and R 2 are both hydrogen, are both methyl or, together, R 1 and R 2 are cyclopropyl.
  • compounds include formula II in which the configuration of the pyrrolidine ring is 3S:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen and (Ci-C 6 ) alkyl or together, R 1 and R 2 form a (C 3 -C 6 ) cycloalkyl.
  • R 3 is selected from hydrogen and (Ci-C 6 ) alkyl.
  • R 4 is selected from a group consisting of optionally substituted heterocyclyl and optionally substituted aryl.
  • R 5 is chosen from a group consisting of optionally substituted heterocyclyl and optionally substituted aryl.
  • Y is a direct bond or -CH 2 or together, Y and R 1 can form a cyclopropane.
  • R 5 when R 5 is pyridinyl or pyrimidinyl, R 1 must be (C 1 -C 6 ) alkyl, and when Y is a direct bond, R 5 is not /? ⁇ r ⁇ -methoxyphenyl or/? ⁇ r ⁇ -chlorophenyl.
  • R 3 is hydrogen. In some embodiments, R 3 is methyl or ethyl. In some embodiments, Y is a direct bond. In some embodiments, Y is a direct bond, R 1 is methyl or ethyl, R 2 is hydrogen, and the R 1 -bearing carbon is in the S configuration. In some embodiments, Y can be -CH 2 or Y and R 1 together can form a cyclopropane.
  • R 4 and R 5 are each optionally substituted aryl.
  • R 4 and R 5 are each phenyl optionally substituted with one or more of hydrogen, trifluoromethyl, halogen, (Ci-C 6 ) alkyl, (C]-C 6 ) alkyloxy, cyano or trifiuoromethoxy.
  • R 4 is a phenyl substituted with one or more of hydrogen, trifluoromethyl, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, cyano or trifiuoromethoxy.
  • R 4 can be napthyl or thiophene.
  • R 5 is a phenyl substituted with one or more of hydrogen, chloro, fluoro, methyl, ethyl, methoxy or ethoxy.
  • R 3 can be optionally substituted napthyl, pyrindin-2-yl, pyrindin-3-yl or indole.
  • R 3 is hydrogen; R 1 is methyl or ethyl; R 2 is hydrogen; Y is a direct bond; R 4 is a phenyl substituted with one or more of hydrogen, trifluoromethyl, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, cyano or trifiuoromethoxy; and R 5 is a phenyl substituted with one or more of hydrogen, chloro, fluoro, methyl, ethyl, methoxy or ethoxy.
  • R 4 is aryl or heteroaryl each optionally substituted by 1 or 2 substituents independently selected from the group consisting of Ci-C 4 alkyl (e.g. methyl), Cj-C 4 alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl and trifluoromethoxy.
  • R 4 is unsubstituted aryl or unsubstituted heteroaryl.
  • R 4 is optionally substituted phenyl or naphthyl. In another embodiment R 4 is phenyl optionally substituted in the para position. In another embodiment R 4 is unsubstituted phenyl or naphthyl.
  • R 4 is optionally substituted pyridinyl, thiophenyl or furanyl.
  • R 5 is aryl or heteroaryl each optionally substituted by 1 or 2 substituents independently selected from the group consisting of CpC 4 alkyl (e.g. methyl), Ci-C 4 alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl and trifluoromethoxy.
  • R 5 is unsubstituted aryl or unsubstituted heteroaryl.
  • R 5 is optionally substituted phenyl. In another embodiment R 5 is phenyl optionally substituted in the ortho or meta positions. In another embodiment R 5 is unsubstituted phenyl.
  • R 5 is optionally substituted pyridinyl, thiophenyl or furanyl.
  • Y is CH 2 In another embodiment Y is a direct bond.
  • R 1 and R 2 are each independently selected from hydrogen or Ci to C 3 alkyl or R 1 and R 2 together form cyclopropyl.
  • R 3 is hydrogen or methyl.
  • salts are pharmaceutically acceptable salts.
  • compounds are in the form of the free base.
  • Some embodiments of the present invention relate to methods of treating or preventing disorders dependent upon the modulation of SSt 4 . Some methods include administering compounds, mixtures or compositionsprovided herein to a subject in need of such treatment. Some embodiments relate to disclosed compounds or mixtures for use in therapy, for the prevention or treatment of pain, inflammatory conditions, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injury and psychiatric disorders comprising administering compounds, mixtures or compositions of the invention to a subject in need of such treatment.
  • compositions and formulations comprising formula I, formula Ib, formula II, and/or mixtures thereof, and a pharmaceutically acceptable carrier.
  • the compositions may be administered alone or in combination with another agent, drug, or hormone, and may be administered by any number of acceptable routes.
  • Compositions suitable for the use can include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
  • Compound (+/-)-4 can also be prepared by using palladium hydroxide catalyst for the debenzylation step. rC
  • Analogous compounds of formula Ia and/or Ib can be synthesized using similar experimental procedures to those described above.
  • the (5)- ⁇ -methyl benzylamine can be replaced with other chiral amines in Procedure F.
  • the corresponding diastereomers resulted form this coupling reaction can be separated accordingly by chromatography.
  • the ⁇ -substituted chiral amines can be prepared from asymmetric synthesis or purchased from commercial sources.
  • Asymmetric syntheses of D -substituted chiral amines are well-known in are.
  • the (S)-l-(2-pyridyl)ethylamine used for Example 10 can be prepared according to a literature procedure (J. Am. Chem. Soc.
  • Example 120 the (S)-l-(5-chlorofuran-2-yl)ethanamine used in Example 120 can be prepared according to the procedure (Tetrahedron Letters 1999, 40, 6709). It is well known that these types of amine can be prepared by more than one method
  • chiral compound of formula I can be prepared by mixing the racemic interemediate XI with a chiral base.
  • the resulting diastereomeric salts may be separated by fractional crystallization and one or both of the diastereomers converted to the corresponding scalemic or pure enantiomers(s) by means well known to one skilled in the art.
  • this scalemic or enantiopure intermediate can be converted into scalemic or enantiopure compounds of formula I using the appropriate procedures summarized above.
  • Procedure K Resolution of (+/-)-/r ⁇ m--l-( ⁇ erM3utoxycarbonyl>4-(4-)
  • (+/-)-tr ⁇ «5-l-(tert-Butoxycarbonyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (+/-)5 (20 g, 55.7 mmol, 1.0 eq., prepared from Procedures A to D) was dissolved in 300 mL DCM (300 mL), (S)-l-phenylethylamine (7 g, 57.8 mmol, 1.04 eq.), EDC (16 g, 83.2 mmol, 1.5 eq.) and HOBt (12 g, 83.2 mmol, 1.5 eq.) were added. The mixture was stirred at 25 0 C for 8 h.
  • (+/-)-tr ⁇ «5-l-(/er/-butoxycarbonyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxylic acid (+/-)5 (15 g, 42 mmol, prepared from Precedures A to D) was dissolved in 200 mL dry THF, (S)-m-methoxy-l-phenylethylamine (7.6 g, 50 mmol; Alfa Aesar, MA, USA), EDC (12.1 g, 63 mmol), HOBt (24 g, 63 mmol) and Et 3 N (10 mL) were added. The mixture was stirred at rt overnight.
  • Example 56 as a white solid (4.7 g, 100%). 1 H NMR Data for Example 56 (see Table 5). Preparation of Example 96 - (3S.4R)-N-((S)-l-m-tolylethylV4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide
  • Racemic 4-methyl-phenylethylamine 18 (20 g, 148 mmol) and N-(I-(R)- phenylethyl)-succinamic acid 17 (33 g, 148 mmol) were dissolved in acetone (120 mL). The mixture allowed to stand at rt for 12 hrs, a white solid 19 (35.7 g) was collected by filtration. To a reaction flask was added the mixture 19 (35.7 g), then it was recrystallized from 170 mL acetone to give the first recrystallization product (18 g). The material was recrystallized two additional time 100 mL and 60 mL acetone to yield the chiral salt 20 (5 g) as a white solid.
  • the chiral salt 20 (5 g, 14 mmol) was dissolved in water (12 mL), 20% aqueous HCl (5 mL) added and the mixture washed by EtOAc (3x 10 mL). To the aqueous phase, NaOH (3 g) was added and extracted by EtOAc (4 ⁇ lO mL). The combined organic phase was dried over Na 2 SO 4 and the solvent evaporated to give the (S)-l-m-tolylethanamine 21 as colorless oil (1.6 g, 8%).
  • the above method can be used to prepare other chiral amines.
  • the chiral amines used in Example 117, 118 and 120 are used in Example 117, 118 and 120.
  • Example 72 was prepared from (-)-5 (prepared from Procedure K) and (S)-l-(6-methoxypyridin-2-yl)ethanamine 51 using the similar procedures in Example 96. 1 H NMR Data for Example 72 (see Table 5). Preparation of Example 91 - (3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide
  • Example 91 according to Procedure G. 1 H NMR Data for Example 91 (see Table 5). Preparation of Example 106 - (3S,4R)-4-(4-ethylphenylVN-((S)-l -(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide
  • Example 106 was prepared from 4- ethylbenzaldehyde 30 (Aldrich, MO, USA) according to Procedure A, B, C2, D, F and G. 1 H NMR Data for Example 106 (see Table 5).
  • HetAr Heteroaryls Preparation of Example 113 - (3S,4S)-4-(5-chlorothiophen-2-ylVN-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide
  • Table 2 shows representative methods to prepare furanylpyrrolidine analogs, and summarizes the general procedures used to prepare three representative examples of furanylpyrrolidine analogs (Example 111, Example 114 and Example 115).
  • the compounds were prepared from commercially available aldehydes using the same or similar procedures reported for previous examples.
  • Table 3 shows representative methods to prepare pyridylpyrrolidine analogs , and summarizes the procedures used to prepare two representative examples of pyridylpyrrolidine analogs (Example 110 and Example 112).
  • the compounds were prepared from commercially available aldehydes using the same or similar procedures reported for previous examples.
  • Method A Waters Millenium Micromass ZQ/2996PDA separations system employing a Phenomenex Luna, 3 ⁇ C 18, 50 x 2.00 mm analytical column.
  • the aqueous acetonitrile based solvent gradient involves:
  • Method B Agilent 1200 LC / 61 10 MSD analytical system employing an Agilent Zorbax SB-Aq, 3.5um, 2.1 x 50 mm analytical column.
  • the aqueous acetonitrile based solvent gradient involves:
  • Method C Waters Millenium 2690/996PDA separations system employing a Phenomenex Columbus 5 ⁇ Cl 8 column 50 x 4.60 mm analytical column.
  • the aqueous acetonitrile based solvent gradient involves:
  • Method D Waters Millenium 2690/996PDA separations system employing a Phenomonex Luna 3 ⁇ C8 50 x 4.6 mm analytical column.
  • the aqueous acetonitrile based solvent gradient involves:
  • Method E Waters Millenium 2690/996PDA separations system employing a Phenomonex Luna 3 ⁇ C8 50 x 4.6 mm analytical column.
  • the aqueous acetonitrile based solvent gradient involves:
  • sst 4 ligands were assessed using a cell membrane-based GTP ⁇ S assay described herein or similar assay known in the art.
  • This functional assay utilizes a Scintillation Proximity Assay (SPA) in a 384-well format with cell membranes containing human sst 4 and test compounds to monitor the GDP to GTP exchange that occurs when this G-protein coupled receptor is activated by an agonist ligand.
  • SPA Scintillation Proximity Assay
  • CHO-Kl cells stably expressing human sst 4 are dounce homogenized in HEPES buffer with protease inhibitor (50 mM HEPES pH 7.4, 1 mM EDTA and IX protease inhibitor cocktail), and the sst 4 containing membranes are purified from the cell lysate by ultracentrifugation in a Beckman 70.1 rotor, 45,000 rpm at 4 0 C for 30 min. Pellets are resuspended in HEPES buffer as described above, and protein determination is performed, after which cell membranes are rapidly frozen in dry-ice and stored at -80 0 C until SPA assay.
  • protease inhibitor 50 mM HEPES pH 7.4, 1 mM EDTA and IX protease inhibitor cocktail
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise.
  • a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.
  • the articles 'a' and 'an' should be construed as referring to one or more than one (i.e., to at least one) of the grammatical objects of the article.
  • 'an element' means one element or more than one element.

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Abstract

L'invention porte sur des composés de pyrrolidine carboxamide comprenant des agonistes de sst4 qui peuvent être utiles pour le traitement et la prévention de la douleur et de troubles inflammatoires.
PCT/US2009/065290 2008-11-21 2009-11-20 Composés de pyrrolidine carboxamide Ceased WO2010059922A1 (fr)

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WO2021170658A1 (fr) * 2020-02-25 2021-09-02 Tes Pharma S.R.L. Composés hétérocycliques pour la modulation de nr2f6
CN113717161A (zh) * 2020-05-21 2021-11-30 广州费米子科技有限责任公司 含氮饱和杂环化合物及其制备方法、药物组合物和应用
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WO2023044326A1 (fr) 2021-09-14 2023-03-23 Eli Lilly And Company Sels agonistes de sstr4
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WO2025247982A1 (fr) 2024-05-29 2025-12-04 Grünenthal GmbH Pipérazines agissant en tant que modulateurs de sstr4

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WO2021170658A1 (fr) * 2020-02-25 2021-09-02 Tes Pharma S.R.L. Composés hétérocycliques pour la modulation de nr2f6
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WO2022012534A1 (fr) * 2020-07-13 2022-01-20 广州费米子科技有限责任公司 Composé hétérocyclique contenant de l'azote, composition pharmaceutique et applications
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