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US20040023974A1 - Cyclic sulfamide derivatives and methods of use - Google Patents

Cyclic sulfamide derivatives and methods of use Download PDF

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Publication number
US20040023974A1
US20040023974A1 US10/405,728 US40572803A US2004023974A1 US 20040023974 A1 US20040023974 A1 US 20040023974A1 US 40572803 A US40572803 A US 40572803A US 2004023974 A1 US2004023974 A1 US 2004023974A1
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thiadiazolidin
ylmethyl
trioxo
benzyl
dioxo
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Inventor
Gary Coppola
John Davies
Charles Jewell
Yu-Chin Li
James Wareing
Donald Sperbeck
Travis Stams
Sidney Topiol
Isidoros Vlattas
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Priority to US10/405,728 priority Critical patent/US20040023974A1/en
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • R 1 is hydrogen, halogen, hydroxy, alkoxy, carboxy, cyano, nitro, trifluoromethyl, alkynyl, alkylthio, heteroaralkyl, heteroaralkoxy or heteroaryloxy provided that R 1 is located at the 2-position when L 3 is —(CHR) s — in which s is zero; or
  • R 1 is optionally substituted alkyl, alkenyl, optionally substituted amino, aralkyl, aralkoxy, aralkylthio, aryloxy, arylthio or cycloalkyl provided that a monocyclic aryl group which is substituted at the para position with a methylene or ethylene bridged nitrogen containing heterocycle does not constitute part of R 1 when
  • R 1 is located at the 2-position and L 3 is —(CHR) s — in which s is zero;
  • C—R 1 may be replaced with nitrogen or N ⁇ O;
  • R 1 and R 2 combined together with the carbon atoms to which R 1 and R 2 are attached form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • R 2 is hydrogen, halogen, hydroxy, alkoxy, cyano, trifluoromethyl, nitro, optionally substituted amino, optionally substituted alkyl, alkylthio, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkylthio, aryloxy, heteroaryloxy, arylthio or cycloalkyl; or
  • R 2 is —C(O)R 3 wherein
  • R 3 is hydroxy or optionally substituted alkoxy
  • R 3 is —NR 4 R 5 in which R 4 and R 5 are independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • L 1 is a single bond
  • L 1 is carbon which combined together with R 2 and the carbon atoms to which L 1 and R 2 are attached form an optionally substituted fused 5- or 6-membered aromatic or heteroaromatic ring provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 1 is CH or nitrogen which taken together with R 2 and the carbon atoms to which L 1 and R 2 are attached form a fused 5- to 7-membered ring which may be interrupted with one or two heteroatoms selected from oxygen, nitrogen and sulfur provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 1 is CH, oxygen, sulfur or nitrogen and L 2 is carbon which combined together with L 1 , R 2 and the carbon atoms to which L 1 and R 2 are attached form an optionally substituted fused 5- or 6-membered aromatic or heteroaromatic ring provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 1 is —CH 2 —, oxygen, sulfur or —NR 6 — and L 2 is CH which taken together with L 1 , R 2 and the carbon atoms to which L 1 and R 2 are attached form a fused 5- to 7-membered ring which may be interrupted with one or two heteroatoms selected from oxygen, nitrogen and sulfur wherein
  • R 6 is hydrogen, optionally substituted alkyl, aralkyl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, sulfonyl or acyl provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 2 is —(CHR 7 ) n — wherein
  • R 7 is hydrogen, hydroxy, alkoxy, carboxy, optionally substituted alkyl, cycloalkyl, aryl or heteroaryl;
  • n is zero or an integer from 1 to 4.
  • Z is —(CHR 8 ) m —, —(CH 2 ) m O(CHR 8 ) r —, —(CH 2 ) m S(CHR 8 ) r — or —(CH 2 ) m NR 9 (CHR 8 ) r — wherein
  • R 8 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl;
  • R 9 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, sulfonyl, acyl or acylamino;
  • m and r are independently zero or an integer of 1 or 2;
  • Q 1 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl provided that
  • Q 1 is not 2-phenyloxazol-4-yl when
  • R 1 and R 2 are hydrogen
  • X and Y are CH;
  • L 1 is a single bond located at the 4-position
  • L 2 is —(CHR 7 ) n — wherein n is zero;
  • L 3 is —(CHR) s — wherein s is zero;
  • Z is —(CH 2 ) m —O(CHR 8 ) r — wherein R 8 is hydrogen, m is zero and r is 2;
  • Q 2 is oxygen
  • R 1 and R 2 are hydrogen
  • X and Y are CH;
  • L 1 is a single bond
  • L 2 is —(CHR 7 ) n — wherein n is zero;
  • L 3 is —(CHR) s — wherein R is hydrogen and s is 1;
  • Z is —(CHR 8 ) m — wherein m is zero;
  • Q 2 is oxygen
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein R 4a and R 5a are as defined for R 4 and R 5 ; R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; q is an integer of 1 or 2; or
  • Q 1 is a radical of the formula
  • W 1 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • W 1 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are as defined for R 4 and R 5 ;
  • R 11 is hydrogen, alkyl or aryl
  • U 1 is —C(O)—, —S(O) 2 — or —(CH 2 ) r — in which r is as defined for Z;
  • V 1 is hydroxy, alkoxy, aryl, heteroaryl, optionally substituted alkyl or cycloalkyl; or
  • V 1 is —NR 4b R 5b in which R 4b and R 5b are as defined for R 4 and R 5 provided that
  • L 2 is —(CHR 7 ) n — in which n is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 2 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are as defined for R 4 and R 5 ;
  • R 11 is hydrogen, alkyl or aryl
  • U 2 is —(CH 2 ) p — in which p is zero or 1;
  • V 2 is —NR 4b C(O)R 5b , —NR 4b C(O)OR 5b , —NR 4b C(O)NR 4c R 5b or —NR 4b S(O) 2 R 5b in which R 4b and R 4c are as defined for R 4 , and R 5b has a meaning as defined for R 5 provided that
  • L 2 is —(CHR 7 ) n — in which n is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 3 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are as defined for R 4 and R 5 ;
  • R 11 is hydrogen, alkyl or aryl
  • U 3 is —(CH 2 ) p — in which p is zero or 1;
  • V 3 is —NHC(O)CHR 4b NHC(O)R 12 wherein R 4b is as defined for R 4 ; R 12 is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl, optionally substituted alkyl, alkoxy or cycloalkyl; or
  • R 12 is —NR 4c R 5b , in which R 4c and R 5b are as defined for R 4 and R 5 provided that
  • L 2 is —(CHR 7 ) n — in which n is an integer of 1 or 2;
  • L 3 is —(CHR) s — wherein
  • R is hydrogen, carboxy, optionally substituted alkyl, cycloalkyl, aryl or heteroaryl;
  • s is zero or an integer from 1 to 3;
  • Q 2 is oxygen, sulfur or NR 13 wherein
  • R 13 is hydrogen, hydroxy or lower alkyl
  • X and Y are independently CH or nitrogen; or
  • —X ⁇ Y— is sulfur, oxygen or —NR 14 — wherein
  • R 14 is hydrogen, optionally substituted alkyl, alkoxycarbonyl, acyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl or sulfonyl;
  • the compounds of the present invention are inhibitors of protein tyrosine phosphatases (PTPases), in particular, the compounds of formula I inhibit PTPase-1B (PTP-1B) and T-cell PTPase (TC PTP), and thus may be employed for the treatment of conditions mediated by PTPase activity.
  • PTPases protein tyrosine phosphatases
  • the compounds of the present invention may also be employed as inhibitors of other enzymes characterized with a phosphotyrosine binding region such as the SH2 domain. Accordingly, the compounds of formula I may be employed for prevention or treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
  • the compounds of the present invention may also be employed in the treatment, prevention or control of a number of conditions that accompany Type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated.
  • the compounds of the present invention may be employed to treat or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system.
  • optionally substituted alkyl refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
  • exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
  • lower alkyl refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkenyl refers to any of the above alkyl groups having at least 2 carbon atoms and containing a carbon to carbon double bond at the point of attachment. Groups having 2 to 4 carbon atoms are preferred.
  • alkynyl refers to any of the above alkyl groups having at least two carbon atoms and containing a carbon to carbon triple bond at the point of attachment. Groups having 2 to 4 carbon atoms are preferred.
  • cycloalkyl refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbon atoms, each of which may be substituted by one or more substituents such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.
  • Exemplary monocyclic hydrocarbon groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • alkoxy refers to alkyl-O—.
  • alkanoyl refers to alkyl-C(O)—.
  • alkanoyloxy refers to alkyl-C(O)—O—.
  • alkylamino and “dialkylamino” refer to alkyl-NH— and (alkyl) 2 N—, respectively.
  • alkanoylamino refers to alkyl-C(O)—NH—.
  • alkylthio refers to alkyl-S—
  • alkylaminothiocarbonyl refers to alkyl-NHC(S)—.
  • alkylthiono refers to alkyl-S(O)—.
  • alkylsulfonyl refers to alkyl-S(O) 2 —.
  • alkoxycarbonyl refers to alkyl-O—C(O)—.
  • alkoxycarbonyloxy refers to alkyl-O—C(O)O—.
  • carboxycarbonyl refers to HO—C(O)C(O)—.
  • carbamoyl refers to H 2 NC(O)—, alkyl-NHC(O)—, (alkyl) 2 NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—, alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and the like.
  • sulfamoyl refers to H 2 NS(O) 2 —, alkyl-NHS(O) 2 —, (alkyl) 2 NS(O) 2 —, aryl-NHS(O) 2 —, alkyl(aryl)-NS(O) 2 —, (aryl) 2 NS(O) 2 —, heteroaryl-NHS(O) 2 —, aralkyl-NHS(O) 2 —, heteroaralkyl-NHS(O) 2 — and the like.
  • sulfonamido refers to alkyl-S(O) 2 —NH—, aryl-S(O) 2 —NH—, aralkyl-S(O) 2 —NH—, heteroaryl-S(O) 2 —NH—, heteroaralkyl-S(O) 2 —NH—, alkyl-S(O) 2 -N(alkyl)-, aryl-S(O) 2 —N(alkyl)-, aralkyl-S(O) 2 —N(alkyl)-, heteroaryl-S(O) 2 —N(alkyl)-, heteroaralkyl-S(O) 2 —N(alkyl)- and the like.
  • sulfonyl refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
  • optionally substituted amino refers to a primary or secondary amino group which may optionally be substituted by a substituent such as acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carboxycarbonyl, carbamoyl, alkylaminothiocarbonyl, arylaminothiocarbonyl and the like.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocyclyl and the like.
  • monocyclic aryl refers to optionally substituted phenyl as described under aryl.
  • aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
  • aralkanoyl refers to aralkyl-C(O)—.
  • aralkylthio refers to aralkyl-S—.
  • aralkoxy refers to an aryl group bonded directly through an alkoxy group.
  • arylsulfonyl refers to aryl-S(O) 2 —.
  • arylthio refers to aryl-S—.
  • aroyl refers to aryl-C(O)—.
  • aroylamino refers to aryl-C(O)—NH—.
  • aryloxycarbonyl refers to aryl-O—C(O)—.
  • heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
  • the heterocyclic group may be attached at a heteroatom or a carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl,
  • Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, benzodiazepinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]-pyridiny
  • Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.
  • heterocyclyl includes substituted heterocyclic groups.
  • Substituted heterocyclic groups refer to heterocyclic groups substituted with 1, 2 or 3 of the following:
  • alkoxycarbonyl such as unsubstituted lower alkoxycarbonyl
  • heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
  • heteroaryl refers to an aromatic heterocycle, for example monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by e.g. lower alkyl, lower alkoxy or halo.
  • heteroarylsulfonyl refers to heteroaryl-S(O) 2 —.
  • heteroaroyl refers to heteroaryl-C(O)—.
  • heteroaroylamino refers to heteroaryl-C(O)NH—.
  • heteroarylkyl refers to a heteroaryl group bonded through an alkyl group.
  • heteroaralkanoyl refers to heteroaralkyl-C(O)—.
  • heteroaralkanoylamino refers to heteroaralkyl-C(O)NH—.
  • acyl refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl and the like.
  • acylamino refers to alkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.
  • salts of any compound of the present invention refer to salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)-methyl-ammonium salts, and salts with amino acids.
  • bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)-methyl-ammonium salts, and salts with amino acids.
  • acid addition salts such as those formed with mineral acids, organic carboxylic acids and organic sulfonic acids e.g. hydrochloric acid, maleic acid and methanesulfonic acid, are possible provided a basic group, such as pyridyl, constitutes part of the structure
  • Prodrug derivatives of any compound of the invention are derivatives of said compounds which following administration release the parent compound in vivo via some chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • exemplary prodrug derivatives are, e.g., esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as defined herein.
  • ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters such as the ⁇ -(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the ⁇ -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester, and the like conventionally used in the art.
  • lower alkyl esters e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters such as the ⁇ -(amino, mono
  • the present invention provides cyclic sulfamide derivatives, preferably 1,1-dioxo-1,2,5-thiadiazolidine derivatives, of formula I, pharmaceutical compositions containing them, methods for preparing such compounds and methods of treating conditions associated with PTPase activity, in particular, PTP-1B and TC PTP activity, by administration of a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • the compounds of the present invention may also be employed in combination with ligands for other enzymes characterized with a phosphotyrosine binding region such as the SH2 domain.
  • Q 2 is oxygen
  • X and Y are CH; or
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl, alkylthio, heteroaralkyl or heteroaralkoxy provided that R 1 is located at the 2-position when L 3 is —(CHR) s — in which s is zero; or
  • R 1 is optionally substituted alkyl, aralkyl, aralkoxy or aryloxy provided that a monocyclic aryl group which is substituted at the para position with a methylene or ethylene bridged nitrogen containing heterocycle does not constitute part of R 1 when
  • R 1 is located at the 2-position and L 3 is —(CHR) s — in which s is zero;
  • R 2 is hydrogen
  • R 2 is —C(O)R 3 wherein
  • R 3 is hydroxy or optionally substituted alkoxy
  • R 3 is —NR 4 R 5 in which R 4 and R 5 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • L 1 is a single bond
  • L 1 is carbon which combined together with R 2 and the carbon atoms to which L 1 and R 2 are attached form an optionally substituted fused 5- or 6-membered aromatic or heteroaromatic ring provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 1 is CH or nitrogen which taken together with R 2 and the carbon atoms to which L 1 and R 2 are attached form a fused 5- to 7-membered ring which may be interrupted with one or two heteroatoms selected from oxygen, nitrogen and sulfur provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 1 is CH, oxygen, sulfur or nitrogen and L 2 is carbon which combined together with L 1 , R 2 and the carbon atoms to which L 1 and R 2 are attached form an optionally substituted fused 5- or 6-membered aromatic or heteroaromatic ring provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 1 is —CH 2 —, oxygen, sulfur or —NR 6 — and L 2 is CH which taken together with L 1 , R 2 and the carbon atoms to which L 1 and R 2 are attached form a fused 5- to 7-membered ring which may be interrupted with one or two heteroatoms selected from oxygen, nitrogen and sulfur wherein
  • R 6 is hydrogen, optionally substituted alkyl, aralkyl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, sulfonyl or achyl provided that L 1 and R 2 are attached to carbon atoms adjacent to each other; or
  • L 2 is —(CHR 7 ) n — wherein
  • R 7 is hydrogen
  • n is zero or an integer of 1 or 2;
  • Z is —(CHR 8 ) m —, —(CH 2 ) m O(CHR 8 ) r —, —(CH 2 ) m S(CHR 8 ) r — or —(CH 2 ) m NR 9 (CHR 8 ) r — wherein
  • R 8 is hydrogen or optionally substituted alkyl
  • R 9 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl or acyl;
  • m and r are independently zero or an integer of 1 or 2;
  • Q 1 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl provided that
  • R 1 and R 2 are hydrogen
  • X and Y are CH;
  • L 1 is a single bond located at the 4-position
  • L 2 is —(CHR 7 ) n — wherein n is zero;
  • L 3 is —(CHR) s — wherein s is zero;
  • Z is —(CH 2 ) m O(CHR 8 ) r — wherein R 8 is hydrogen, m is zero and r is 2; or
  • R 1 and R 2 are hydrogen
  • X and Y are CH;
  • L 1 is a single bond
  • L 2 is —(CHR 7 ) n — wherein n is zero;
  • L 3 is —(CHR) s — wherein R is hydrogen and s is 1;
  • Z is —(CHR 8 ) m — wherein m is zero;
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein R 4a and R 5a are as defined for R 4 and R 5 ; R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; q is an integer of 1 or 2; or
  • Q 1 is a radical of the formula
  • W 1 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • W 1 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are as defined for R 4 and R 5 ;
  • R 11 is hydrogen, alkyl or aryl
  • U 1 is —C(O)— or —(CH 2 ) r — in which r is as defined for Z;
  • V 1 is hydroxy, alkoxy, aryl, heteroaryl, optionally substituted alkyl or cycloalkyl; or
  • V 1 is —NR 4b R 5b in which R 4b and R 5b are as defined for R 4 and R 5 provided that
  • L 2 is —(CHR 7 ) n — in which n is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 2 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are as defined for R 4 and R 5 ;
  • R 11 is hydrogen, alkyl or aryl
  • U 2 is —(CH 2 ) p — in which p is zero or 1;
  • V 2 is —NR 4b C(O)R 5b , —NR 4b C(O)OR 5b , —NR 4b C(O)NR 4c R 5b or —NR 4b S(O) 2 R 5b in which R 4b and R 4c are as defined for R 4 , and R 5b has a meaning as defined for R 5 provided that
  • L 2 is —(CHR 7 ) n — in which n is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 3 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are as defined for R 4 and R 5 ;
  • R 11 is hydrogen, alkyl or aryl
  • U 3 is —(CH 2 ) p — in which p is zero or 1;
  • V 3 is —NHC(O)CHR 4b NHC(O)R 12 wherein R 4b is as defined for R 4 ; R 12 is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl, optionally substituted alkyl, alkoxy or cycloalkyl; or
  • R 12 is —NR 4c R 5b , in which R 4c and R 5b are as defined for R 4 and R 5 provided that
  • L 2 is —(CHR 7 ) n — in which n is an integer of 1 or 2;
  • L 3 is —(CHR) s — wherein
  • R is hydrogen
  • s is zero or an integer from 1 to 3;
  • X and Y are CH, or
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl, optionally substituted alkyl, alkylthio, aralkyl, aralkoxy, aryloxy, heteroaralkyl or heteroaralkoxy;
  • n is zero or an integer of 1 or 2;
  • Z is —(CHR 8 ) m —, —(CH 2 ) m O(CHR 8 ) r —, —(CH 2 ) m S(CHR 8 ) r — or —(CH 2 ) m NR 9 (CHR 8 ) r — wherein
  • R 8 is hydrogen
  • R 9 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl or acyl;
  • m and r are independently zero or an integer of 1 or 2;
  • Q 1 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein
  • R 4a and R 5b are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • q is an integer of 1 or 2;
  • s is zero or an integer of 1 or 2;
  • Q 3 is O, S or —NR 6a — wherein
  • R 6a is hydrogen, optionally substituted alkyl, aralkyl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, sulfonyl or acyl;
  • X and Y are CH; or
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl, optionally substituted alkyl, alkylthio, aralkyl, aralkoxy, aryloxy, heteroaralkyl or heteroaralkoxy;
  • Z is —(CHR 8 ) m —, —(CH 2 ) m O(CHR 8 ) r —, —(CH 2 ) m S(CHR 8 ) r — or —(CH 2 ) m NR 9 (CHR 8 ) r — wherein
  • R 8 is hydrogen
  • R 9 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl or acyl;
  • m and r are independently zero or an integer of 1 or 2;
  • Q 1 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein
  • R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • q is an integer of 1 or 2;
  • s is zero or an integer of 1 or 2;
  • Q 3 is O, S or —NR 6a — wherein
  • R 6a is hydrogen, optionally substituted alkyl, aralkyl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, sulfonyl or acyl;
  • X and Y are CH; or
  • R 2 is hydrogen
  • L 1 is a single bond
  • L 2 is —(CH 2 ) n — in which n is zero or an integer of 1 or 2;
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl or alkylthio provided that R 1 is located at the 2-position when s is zero; or
  • R 1 is optionally substituted alkyl, aralkyl, aralkoxy or aryloxy provided that a monocyclic aryl group which is substituted at the para position with a methylene or ethylene bridged nitrogen containing heterocycle does not constitute part of R 1 when
  • R 1 is located at the 2-position and s is zero;
  • n is zero or an integer of 1 or 2;
  • s is zero or 1;
  • Z is —(CHR 8 ) m —, —(CH 2 ) m O(CHR 8 ) r —, —(CH 2 ) m S(CHR 8 ) r ' or —(CH 2 ) m NR 9 (CHR 8 ) r — wherein
  • R 8 is hydrogen
  • R 9 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or acyl;
  • m and r are independently zero or an integer of 1 or 2;
  • Q 1 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl provided that
  • R 1 is hydrogen
  • X and Y are CH;
  • n is zero;
  • Z is 13 (CH 2 ) m O(CHR 8 ) r — wherein R 8 is hydrogen, m is zero and r is 2; or
  • R 1 is hydrogen
  • X and Y are CH;
  • n is zero;
  • Z is —(CHR 8 ) m — wherein m is zero;
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein
  • R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • q is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 1 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • W 1 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 11 is hydrogen, alkyl or aryl
  • U 1 is —C(O)— or —(CH 2 ) r — in which r is as defined for Z;
  • V 1 is hydroxy, alkoxy, aryl, heteroaryl, optionally substituted alkyl or cycloalkyl; or
  • V 1 is —NR 4b R 5b in which R 4b and R 5b are as defined for R 4a and R 5a provided that
  • n is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 2 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 11 is hydrogen, alkyl or aryl
  • U 2 is —(CH 2 ) r — in which p is zero or 1;
  • V 2 is —NR 4b C(O)R 5b , —NR 4b C(O)OR 5b , —NR 4b C(O)NR 4c R 5b or —NR 4b S(O) 2 R 5b in which R 4b and R 4c are as defined for R 4a , and R 5b has a meaning as defined for R 5a provided that
  • n is an integer of 1 or 2;
  • Q 1 is a radical of the formula
  • W 3 is —C(O)R 3a in which R 3a is hydroxy or optionally substituted alkoxy; or
  • R 3a is —NR 4a R 5a in which R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 11 is hydrogen, alkyl or aryl
  • U 3 is —(CH 2 ) r — in which r is zero or 1;
  • V 3 is —NHC(O)CHR 4b NHC(O)R 12 wherein R 4b is as defined for R 4a ; R 12 is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl, optionally substituted alkyl, alkoxy or cycloalkyl; or
  • R 12 is —NR 4c R 5b in which R 4c is as defined for R 4a , and R 5b has a meaning as defined for R 5a provided that
  • n is an integer of 1 or 2;
  • X and Y are CH; or
  • R 1 is bromide
  • X and Y are CH;
  • n is zero;
  • Z is —(CH 2 ) m — in which m is zero;
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein
  • R 4a and R 5b are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • q is an integer of 1 or 2;
  • n is an integer of 1 or 2;
  • Z is —(CH 2 ) m —, —(CH 2 ) m O(CH 2 ) r — or —(CH 2 ) m S(CH 2 ) r — wherein
  • r is zero or 1;
  • Q 1 is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl;
  • n is an integer of 1 or 2;
  • Z is —(CH 2 ) m NR 9 (CH 2 ) r — wherein
  • R 9 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or acyl;
  • r is zero or 1;
  • Q 1 is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or
  • Q 1 is —C(O)NR 4a R 5a , —C(O)R 10 , —C(O)OR 10 or —S(O) q R 10 wherein
  • R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 10 is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • q is an integer of 1 or 2;
  • n is an integer of 1 or 2;
  • Z is —(CH 2 ) m — wherein m is zero;
  • Q 1 is a radical of the formula
  • W 1 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • R 11 is hydrogen, alkyl or aryl
  • U 1 is —C(O)— or —(CH 2 ) r — in which r is zero;
  • V 1 is aryl, heteroaryl, optionally substituted alkyl or cycloalkyl
  • n 1;
  • Z is —(CH 2 ) m — wherein m is zero;
  • Q 1 is a radical of the formula
  • W 2 is —C(O)R 3a in which R 3a is —NR 4a R 5a , and R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 11 is hydrogen
  • U 2 is —(CH 2 ) p — in which p is zero;
  • V 2 is —NR 4b C(O)R 5b , —NR 4b C(O)OR 5b , —NR 4b C(O)NR 4c R 5b or —NR 4b S(O) 2 R 5b in which R 4b and R 4c are as defined for R 4a , and R 5b has a meaning as defined for R 5a ;
  • n 1;
  • Z is —(CH 2 ) m — wherein m is zero;
  • Q 1 is a radical of the formula
  • W 3 is —C(O)R 3a in which R 3a is —NR 4a R 5a , and R 4a and R 5a are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;
  • R 1 is hydrogen
  • U 3 is —(CH 2 ) p — in which p is zero;
  • V 3 is —NHC(O)CHR 4b NHC(O)R 12 wherein R 4b is as defined for R 4a ; R 12 is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl, optionally substituted alkyl or alkoxy; or
  • R 12 is —NR 4c R 5b in which R 4c and R 5b are as defined for R 4a and R 5a ;
  • Pg is an appropriate N-protecting group such as 4-methoxybenzyl, 2,4-dimethoxybenzyl or 2-trimethylsilylethyl
  • R 15 is hydrogen to afford compounds of the formula
  • Pg has a meaning as defined herein above
  • a coupling agent such as diisopropyl carbodiimide (DIC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) in the presence a base such as triethylamine (TEA) or N-methyl-morpholine (NMM) in an organic solvent such as tetrahydrofuran (THF), N,N-dimethyl-formamide (DMF) or dichoromethane (CH 2 Cl 2 ).
  • THF tetrahydrofuran
  • DMF N,N-dimethyl-formamide
  • CH 2 Cl 2 dichoromethane
  • the reaction may be carried out in the presence of an additive such as of hydroxybenzotriazole (HOBt).
  • HOBt hydroxybenzotriazole
  • L 3 is —(CHR) s — in which s is an integer of 1 to 3; L 1 , L 2 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 respectively, under Mitsunobu conditions, e.g., in the presence of reagents such as triphenylphosphine and diethyl azodicarboxylate in an organic solvent such as THF to form compounds of the formula
  • L 3 is —(CHR) s — in which s is an integer of 1 to 3; Pg, L 1 , L 2 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively.
  • compounds of formula V wherein L 3 is —(CHR) s — in which s is an integer of 1 to 3; Pg, L 1 , L 2 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 , as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively, may be obtained by condensing a compound of formula III wherein Pg has a meaning as defined herein with an alkylating agent of the formula
  • L 3 is —(CHR) s — in which s is an integer of 1 to 3;
  • Lg 1 represents a leaving group, such as chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate;
  • L 1 , L 2 , X and Y have meanings as defined herein;
  • R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or
  • R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , in the presence of a base such as 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) in an inert solvent such as CH 2 Cl 2 , THF or DMF to afford compounds of formula V.
  • DBU 1,8-diazabicyclo[5,4,0]-undec-7
  • L 1 , L 2 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively, in the presence of a copper catalyst such as copper(II) acetate and a base such as cesium(II) carbonate (Ce 2 CO 3 ) or TEA in an organic solvent such as THF, 1,4-dioxane or CH 2 Cl 2 to afford compounds of the formula V wherein wherein L 3 is —(CHR) s — in which s is zero; Pg, L 1 , L 2 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as
  • Lg 2 represents a leaving group such as halide or trifluoromethanesulfonate, preferably fluoride or chloride;
  • L 1 , L 2 , X and Y have meanings as defined herein; and
  • R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or
  • R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively, using conditions well know in the art or using methods described herein or modifications thereof, e.g., a compound of formula III may be first treated with a base such as Ce 2 CO 3 , or sodium, lithium or potassium bis(trimethylsilyl)amide in an inert organic solvent such as THF or 1,4-dioxane followed by reaction with a compound of formula VIb at a temperature ranging from room temperature (RT) to 110° C.
  • a base such as Ce 2
  • compounds of formula I′ wherein L 1 , L 2 , L 3 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively, may be prepared by condensing compounds of the formula
  • R 15 is an alkyl group as defined herein; and L 1 , L 2 , L 3 , X, Y, R 1 ′, R 2 ′, Z′ and Q 1 ′ have meanings as defined for formula I′, with a sulfamoyl chloride analog of the formula
  • R 16 is hydrogen or alkoxycarbonyl such as t-butoxycarbonyl or 2-trimethylsilyl-ethoxycarbonyl, in the presence of a base such as TEA or NMM in an organic solvent such as acetonitrile (MeCN), CH 2 Cl 2 or THF to form compounds of the formula
  • R 15 , R 16 , L 1 , L 2 , L 3 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively.
  • Compounds of formula VIII wherein R 16 is alkoxycarbonyl may be obtained by reacting chlorosulfonyl isocyanate with the appropriate alcohol in an organic solvent such as MeCN, CH 2 Cl 2 or THF.
  • L 1 , L 2 , L 3 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively, with an acetate of the formula
  • Lg 1 and R 15 have meanings as defined herein, in the presence of a base such as TEA or NMM in an inert solvent such as THF or 1,4-dioxane.
  • Amines of formula X may be obtained according to methods well known in the art, e.g, as described in PCT Patent Application Publications WO/9946236, WO/9946244, WO/9946268, WO/0119830, WO/0119831, WO/0204458 and WO/0204459, or using methods described herein in the Examples, or modifications thereof.
  • L 1 , L 2 , L 3 , X and Y have meanings as defined herein; and R 1 ′, R 2 ′, Z′ and Q 1 ′ represent R 1 , R 2 , Z and Q 1 as defined herein; or R 1 ′, R 2 ′, Z′ and Q 1 ′ are groups convertible to R 1 , R 2 , Z and Q 1 , respectively.
  • Compound of formula XII may then be converted to compound of formula IX in which R 16 is hydrogen by the reaction with acetates of formula XI in the presence of a base such as sodium hydride in an inert solvent such as THF or DMF.
  • compounds of formula XIII may be converted to compounds of formula XIV by treatment with an alkylating agent of the formula Pg-Lg 1 in which Pg and Lg 1 have meanings as defined herein, in the presence of a base such as DBU in an inert solvent such as CH 2 Cl 2 , THF or DMF.
  • a base such as DBU
  • an inert solvent such as CH 2 Cl 2 , THF or DMF.
  • the subsequent reaction between compounds of formula XIV and the organozinc reagent XV may be carried out in the presence of palladium(O) catalyst such as tris(dibenzylideneacetone)-dipalladium(O) acetate and a phosphine ligand such as tritolylphosphine in an organic solvent such as DMF to form compounds of formula XVI.
  • palladium(O) catalyst such as tris(dibenzylideneacetone)-dipalladium(O) acetate
  • Compounds of formula XVI may be treated with an acid such as TFA to remove the t-butoxycarbonyl protecting group.
  • the resulting amines, or acid addition salts thereof are then reacted with a N-derivatizing agent, such as an activated derivative of a carboxylic acid, a chloroformate, an isocyanate or a sulfonyl chloride, in the presence of a base such as TEA, diisopropylethylamine or NMM in an inert solvent such as MeCN, CH 2 Cl 2 , DMF or THF to obtain compounds of formula XVII wherein R 17 is —C(O)R 5b , —C(O)OR 5b , —C(O)NR 4c R 5b or —S(O) 2 R 5b , respectively, and R 4c and R 5b have meanings as defined herein.
  • the benzyl ester may then be removed, e.g., by catalytic hydrogenation, to afford carboxylic acids of formula XVIII.
  • Coupling of an activated derivative of a carboxylic acid of formula XVIII with amines of the formula HNR 4a R 5a yields amides of formula XIX wherein R 4a and R 5a have meanings as defined herein.
  • treatment with TFA affords compounds of formula I′′.
  • activated derivatives of carboxylic acids include acid chlorides, bromides and fluorides, mixed anhydrides, lower alkyl esters, and activated esters thereof, and adducts formed with coupling agents such as EDCI, DIC, O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and the like.
  • Mixed anhydrides are preferably such from pivalic acid, or lower alkyl hemiesters of carbonic acids, such as ethyl or isobutyl analogs.
  • Activated esters include, for example, succinimido, phthalimido or 4-nitrophenyl esters.
  • the reaction of an activated derivative of a carboxylic acid, e.g., those of formula XVIII, with an amine may be carried out in the presence of a base such as TEA, diisopropylethylamine or NMM in an inert solvent such as CH 2 Cl 2 , DMF or THF.
  • Carboxylic acids e.g. those of formula XVIII, can be converted to their activated derivatives using methods described herein or modifications thereof or using methods well known in the art.
  • Compounds of formula XXII may be converted to compounds of formula XXIII by the treatment with a brominating agent, e.g., dibromo isocyanuric acid, in an organic solvent such as THF or 1,4-dioxane.
  • a brominating agent e.g., dibromo isocyanuric acid
  • organic solvent such as THF or 1,4-dioxane.
  • Compounds of formula XXIII may then be reacted with an alcohol of the formula Pg-OH wherein Pg is a suitable N-protecting group as defined herein, under Mitsunobu conditions, e.g., in the presence of triphenylphoshine and diethyl azodicarboxylate in an organic solvent such as THF to afford compounds of formula XXIV.
  • compounds of formula XXIII may be converted to compounds of formula XXIV by treatment with an alkylating agent of the formula Pg-Lg 1 in which Pg has meanings as defined herein and Lg 1 represents a leaving group such as defined herein, in the presence of a base such as DBU in an inert solvent such as CH 2 Cl 2 , THF or DMF.
  • an alkylating agent of the formula Pg-Lg 1 in which Pg has meanings as defined herein and Lg 1 represents a leaving group such as defined herein in the presence of a base such as DBU in an inert solvent such as CH 2 Cl 2 , THF or DMF.
  • protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
  • the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
  • the invention also relates to any novel starting materials, intermediates and processes for their manufacture.
  • the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof.
  • the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
  • Any resulting mixtures of isomers can be separated on the basis of the physico-chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.
  • Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g. by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • the carboxylic acid intermediates can thus be resolved into their optical antipodes e.g. by fractional crystallization of d- or I-(alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts.
  • Racemic products can also be resolved by chiral chromatography, e.g. high pressure liquid chromatography using a chiral adsorbent.
  • compounds of the invention are either obtained in the free form, as a salt thereof if salt forming groups are present or as prodrug derivatives thereof.
  • salts may be converted into salts with pharmaceutically acceptable bases.
  • Such salts include alkali metal salts like sodium. lithium and potassium salts, alkaline earth metal salts like calcium and magnesium salts, ammonium salts with organic bases, e.g., trimethylamine salts, diethylamine salts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts and N-methyl-D-glucamine salts, salts with amino acids like arginine, lysine, and the like.
  • Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g. diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.
  • Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C 1 -C 4 )-alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C 1 -C 4 )-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstit
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit protein tyrosine phosphatases, and for the treatment of conditions associated with PTPase activity, in particular, PTP-1B and TC PTP activity.
  • enteral such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit protein tyrosine phosphatases
  • PTPase activity in particular, PTP-1B and TC PTP activity.
  • Such conditions include insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
  • the compounds of the present invention may also be employed in the treatment, prevention or control of a number of conditions that accompany Type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated.
  • the compounds of the present invention may be employed to treat or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system.
  • the said pharmaceutical compositions comprise a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers.
  • the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising a therapeutically effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
  • Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g.
  • Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to75%, preferably about 1 to 50%, of the active ingredient.
  • Suitable formulations for transdermal application include a therapeutically effective amount of a compound of the invention with carrier.
  • Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the pharmaceutical formulations contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in a combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art.
  • therapeutic agents include insulin; insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; peroxisome proliferator-activated receptor (PPAR ⁇ and/or PPAR ⁇ ) ligands; biguanides such as metformin; aldose reductase inhibitors; alpha-glucosidase inhibitors such as acarbose; glycogen phosphorylase inhibitors; GLP-1 (glucagon like peptide-1); GLP-1 analogs such as Exendin-4; GLP-1 mimetics
  • the methods of treatment or prevention described herein may further include administering to mammals a second anti-diabetic compound in an amount effective to treat or prevent diabetes.
  • the methods of treatment of diabetes may include the administration of a cholesterol biosynthesis inhibitor, particularly, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor such as lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; a squalene synthase inhibitor; or FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid; and aspirin in an amount effective to improve the lipid profile.
  • HMG-CoA 3-hydroxy-3-methyl-glutaryl co
  • a cholesterol lowering agent, anti-hypertensive agent or anti-obesity agent may be beneficial in the treatment or prevention of atherosclerosis, hypertension, obesity and other conditions that often are associated with Type 2 diabetes.
  • a compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • a unit dosage for a mammal of about 50 to 70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5 mg to 500 mg of the active ingredient.
  • the therapeutically effective dosage of a compound of formula I is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved.
  • the compounds of the present invention are inhibitors of PTPases, in particular PTP-1B and TC PTP, and thus may be employed for the treatment of conditions associated with PTPase activity, in particular with PTP-1B and TC PTP activity, as described herein, e.g. insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels, and conditions that accompany Type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is a component.
  • the compounds of this invention may be employed to treat or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system.
  • the above-cited properties are demonstrable in vitro and in vivo tests, using advantageously mammals, e.g. mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • Said compounds can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g. as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 ⁇ 3 molar and 10 ⁇ 9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 1 and 500 mg/kg, preferably between about 5 and 100 mg/kg.
  • the PTP-1B inhibitory activity in vitro may be determined as follows:
  • hPTP-1B human PTP-1B activity in the presence of various agents is determined by measuring the amount of inorganic phosphate released from a phosphopeptide substrate using a 96-well microtiter plate format.
  • the assay (100 ⁇ L) is performed in an assay buffer comprised of 50 mM TRIS (pH 7.5), 50 mM NaCl, 3 mM DTT at ambient temperature.
  • the assay is typically performed in the presence of 0.4% dimethyl sulfoxide (DMSO). However, concentrations as high as 10% are used with certain poorly soluble compounds.
  • DMSO dimethyl sulfoxide
  • a typical reaction is initiated by the addition of 0.4 pmoles of hPTP-1B (amino acids 1-411) to wells containing assay buffer, 3 nmoles of the synthetic phosphopeptide substrate (GNGDpYMPMSPKS), and the test compound. After 10 min, 180 ⁇ L malachite green reagent (0.88 mM malachite green, 8.2 mM ammonium molybdate, aqueous 1N HCl, and 0.01% Triton X-100) is added to terminate the reaction.
  • malachite green reagent (0.88 mM malachite green, 8.2 mM ammonium molybdate, aqueous 1N HCl, and 0.01% Triton X-100
  • Inorganic phosphate a product of the enzyme reaction, is quantitiated after 15 min as the green color resulting from complexing with the Malichite reagent and is determined as an A 620 using a Molecular Devices (Sunnyvale, Calif.) SpectraMAX Plus spectrophotometer. Test compounds are solubilized in 100% DMSO (Sigma, D-8779) and diluted in DMSO. Activity is defined as the net change in absorbance resulting from the activity of the uninhibited hPTP-1B [1-411] minus that of a tube with acid-inactivated hPTP-1B[ 1-411] .
  • the hPTP-1B [1-411] is cloned by PCR from a human hippocampal cDNA library (Clonetech) and inserted into a pET 19-b vector (Novagen) at the Nco1 restriction site.
  • E. coli strain BL21 (DE3) is transformed with this clone and stored as a stock culture in 20% glycerol at ⁇ 80° C.
  • a stock culture is inoculated into Lb/Amp and grown at 37° C.
  • lysis buffer 50 mM Tris, 100 mM NaCl, 5 mM DTT, 0.1% Triton X-100, pH7.6
  • the lysate is centrifuged at 100,000 ⁇ g for 60 min and the supernatant is buffer exchanged and purified on a cation exchange POROS 20SP column followed by an anion exchange Source 30Q (Pharmacia) column, using linear NaCl gradient elutions.
  • Enzyme is pooled, adjusted to 1 mg/mL and frozen at ⁇ 80° C.
  • Ligand binding is detected by acquiring 1 H- 15 N HSQC spectra on 250 ⁇ L of 0.15 mM PTP-1B [1-298] in the presence and absence of added compound (1-2 mM). The binding is determined by the observation of 15 N- or 1 H-amide chemical shift changes in two dimensional HSQC spectra upon the addition of a compound to 15 N-label protein. Because of the 15 N spectral editing, no signal from the ligand is observed, only protein signals. Thus, binding can be detected at high compound concentrations. Compounds which caused a pattern of chemical shift changes similar to the changes seen with known active site binders are considered positive.
  • Diafiltration using a 10 kD MWCO membrane is used to buffer exchange the protein and reduce the NaCl concentration prior to cation exchange chromatography.
  • Diafiltration buffer contained 50 mM MES, 75 mM NaCl, 5 mM DTT, pH 6.5. Soluble supernatant is then loaded onto a POROS 20 SP (1 ⁇ 10 cm) column equilibrated with cation exchange buffer (50 mM MES and 75 mM NaCl, pH 6.5) at a rate of 20 mL/min. Protein is eluted from the column using a linear salt gradient (75-500 mM NaCl in 25 CV). Fractions containing PTP-1B's are identified and pooled according to SDS-PAGE analyses.
  • PTP-1B 1-298 is further purified by anion exchange chromatography using a POROS 20 HQ column (1 ⁇ 10 cm).
  • the pool from cation exchange chromatography is concentrated and buffer exchanged in 50 mM Tris-HCl, pH 7.5 containing 75 mM NaCl and 5 mM DTT.
  • Protein is loaded onto column at 20 mL/min and eluted using a linear NaCl gradient (75-500 mM in 25 CV).
  • Final purification is performed using Sephacryl S-100 HR (Pharmacia)(50 mM HEPES, 100 mM NaCl, 3 mM DTT, pH 7.5 ).
  • the TC PTP activity may be measured, e.g., according to a method described by Peters et. al. J. Biol. Chem, 2000, 275, 18201-09.
  • the glucose and insulin lowering activity in vivo may be evaluated as follows:
  • mice (Jackson Lab, Bar Harbor, Md.) at the age of 11 weeks are housed six per cage in a reversed light cycle room (light on from 6:00 p.m. to 6:00 a.m.) and given access to Purina rodent chow and water ad libitum.
  • tail blood samples are taken at 8:00 am and plasma glucose levels are determined.
  • the animals are randomly assigned to the control and compound groups. The means of plasma glucose values of the groups are matched. Animals are then orally dosed with vehicle (0.5% carboxymethyl-cellulose with 0.2% Tween-80) or compounds (at 30 mg/kg) in vehicle.
  • the mice are dosed daily for a total of 3 days.
  • basal blood samples are taken.
  • the plasma samples are analyzed for glucose concentrations using a YSI2700 Dual Channel Biochemistry Analyzer (Yellow Springs Instrument Co., Yellow Springs, Ohio) and insulin concentrations using an ELISA assay.
  • the resin is drained and washed successively with DMF (20 mL, 3 times), MeOH (20 mL, 2 times), THF (20 mL, 1 time) and alternatively with CH 2 Cl 2 (20 mL, 3 times) and MeOH (20 mL, 2 times).
  • the resin is dried under high vacuum overnight.
  • the dry Wang resin-Fmoc-glycine ester (140 mg, 0.106 mmol) is treated with 20% piperidine in CH 2 Cl 2 (3 mL, 15 min, 2 times) and washed alternatively with CH 2 Cl 2 (3 mL, 2 times) and MeOH (3 mL, 2 times) and again with CH 2 Cl 2 (3 mL, 2 times).
  • the resin is then suspended in CH 2 Cl 2 —MeOH (1:1, 4 mL), and the title A compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid (133 mg, 0.317 mmol), benzaldehyde (32 ⁇ l, 0.317 mmol) and butylisonitrile (33 ⁇ l, 0.317 mmol) are added and the mixture is shaken for 48 h.
  • the resin is drained and is washed alternatively with CH 2 Cl 2 (4 mL, 2 times), MeOH (4 mL, 2 times) and again with CH 2 Cl 2 (4 mL, 2 times).
  • the resin is then shaken with CH 2 Cl 2 -TFA (1:1, 4 mL) for 4 h and drained into a receiving flask.
  • the resin is washed with CH 2 Cl 2 -TFA (1:1, 4 mL) and drained into the same receiving flask.
  • the solvents are evaporated to dryness under a stream of nitrogen and the residue is further dried under high vacuum.
  • DBU (127 mg, 0.836 mmol) is added slowly to a suspension of the title B compound, 4-bromomethyl-benzoic acid 2-ethyl-butyl ester (250 mg, 0.836 mmol) and the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg, 0.836 mmol) in 10 mL of CH 2 Cl 2 at RT. The resulting solution is stirred at RT overnight.
  • HOBt 28 mg, 0.179 mmol
  • pentyl amine 0.021 mL, 0.179 mmol
  • EDCI 38 mg, 0.198 mmol
  • (S)-2-t-butoxycarbonyl-amino-3- ⁇ 3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl ⁇ -propionic acid (96 mg, 0.179 mmol) in CH 2 Cl 2 (4 mL) at RT. After 2 h, the reaction is concentrated and the residue is taken up in EtOAc.

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040167187A1 (en) * 2002-12-30 2004-08-26 Saunders Jeffrey O. Sulfhydantoins as phosphate isosteres
US20040186151A1 (en) * 2003-02-12 2004-09-23 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
US20040192743A1 (en) * 2003-02-12 2004-09-30 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
US20050187277A1 (en) * 2004-02-12 2005-08-25 Mjalli Adnan M. Substituted azole derivatives, compositions, and methods of use
US20080293782A1 (en) * 2005-12-08 2008-11-27 David Barnes 1,1,3-Trioxo-1,2,5-Thiadiazolidines and Their Use as Ptp-Ases Inhibitors
US20090181928A1 (en) * 2006-03-31 2009-07-16 Alan Neubert Organic compounds
US20100113331A1 (en) * 2006-01-30 2010-05-06 Transtech Pharma, Inc. Substituted Imidazole Derivatives, Compositions, and Methods of Use as PtPase Inhibitors

Families Citing this family (19)

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US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
BRPI0612582A2 (pt) * 2005-07-01 2010-11-23 Novartis Ag combinação de compostos orgánicos
UA94921C2 (en) * 2005-12-08 2011-06-25 Новартис Аг 1-orthofluorophenyl substituted 1, 2, 5-thiazolidinedione derivatives as ptp-as inhibitors
UA94724C2 (en) * 2005-12-08 2011-06-10 Новартис Аг Thiadiazolidinone derivatives as antidiabetic agents
CN101312957A (zh) * 2005-12-08 2008-11-26 诺瓦提斯公司 用于治疗由蛋白酪氨酸磷酸酶介导的疾病(ptpase)的1,2,5-噻唑烷衍生物
PL1984344T3 (pl) * 2005-12-29 2013-03-29 Lexicon Pharmaceuticals Inc Multicykliczne pochodne aminokwasów oraz sposób ich stosowania
WO2008067527A1 (en) * 2006-12-01 2008-06-05 Novartis Ag Inhibitors of protein tyrosine phosphatase for the treatment of muscle atrophy and related disorders
AR066820A1 (es) * 2007-06-04 2009-09-16 Novartis Ag Compuestos de tiadiazolidin-3 ona
WO2011062766A2 (en) * 2009-11-17 2011-05-26 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
WO2012038943A1 (en) 2010-09-24 2012-03-29 Ranbaxy Laboratories Limited Matrix metalloproteinase inhibitors
US9040525B2 (en) 2010-10-08 2015-05-26 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
CA2834465A1 (en) 2011-04-28 2012-11-01 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
BR112015023571A2 (pt) * 2013-03-15 2017-07-18 Hoffmann La Roche derivados de sulfamato e sulfamida de arila como moduladores rorc
WO2019246513A1 (en) * 2018-06-21 2019-12-26 Calico Life Sciences Llc Protein tyrosine phosphatase inhibitors and methods of use thereof
US20250041272A1 (en) * 2021-11-03 2025-02-06 The University Of North Carolina At Chapel Hill Compositions and methods for treating cancer via ptp1b inhibition
WO2024067802A1 (zh) * 2022-09-30 2024-04-04 深圳众格生物科技有限公司 蛋白酪氨酸磷酸酶抑制剂及其制备方法和医药用途
WO2024141015A1 (en) * 2022-12-30 2024-07-04 Insilico Medicine Ip Limited Protein tyrosine phosphatase inhibitors and uses thereof

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9104136D0 (en) * 1991-02-27 1991-04-17 Merck Sharp & Dohme Therapeutic agents
CA2062558A1 (en) * 1991-03-08 1992-09-09 Prasun K. Chakravarty Heterocyclic compounds bearing acidic functional groups as angiotensin ii antagonists
WO1992020662A1 (en) * 1991-05-10 1992-11-26 Merck & Co., Inc. Acidic aralkyl triazole derivatives active as angiotensin ii antagonists
US5238942A (en) 1991-05-10 1993-08-24 Merck & Co., Inc. Substituted quinazolinones bearing acidic functional groups as angiotensin ii antagonists
US5223501A (en) 1991-05-10 1993-06-29 Merck & Co., Inc. Substituted pyrimidinones bearing acidic functional groups as angiotensin ii antagonists
US5162340A (en) * 1991-05-10 1992-11-10 Merck & Co., Inc. Substituted 1-(2h)-isoquinolinones bearing acidic functional groups as angiotensin ii antagonists
US5958957A (en) * 1996-04-19 1999-09-28 Novo Nordisk A/S Modulators of molecules with phosphotyrosine recognition units
JP2000511883A (ja) * 1996-04-19 2000-09-12 ノボ ノルディスク アクティーゼルスカブ ホスホチロシン認識ユニットを有する分子のモジュレーター
FR2764889B1 (fr) * 1997-06-20 2000-09-01 Sod Conseils Rech Applic Nouveaux derives du 2-(iminomethyl)amino-phenyle, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant
US6420401B1 (en) * 1997-08-22 2002-07-16 Wichita State University 1,2,5, thiadiazolidin-3-one 1,1-dioxide derivatives
AU2825899A (en) 1998-03-12 1999-09-27 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
WO1999046244A1 (en) 1998-03-12 1999-09-16 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
WO1999046236A1 (en) 1998-03-12 1999-09-16 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
JP2003509430A (ja) 1999-09-10 2003-03-11 ノボ ノルディスク アクティーゼルスカブ プロテインチロシンホスファターゼ（ｐｔｐアーゼ）のモジュレーター
AU6985200A (en) 1999-09-10 2001-04-17 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
AU2001268951A1 (en) 2000-07-07 2002-01-21 Novo-Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
DE60118195T2 (de) 2000-07-07 2006-12-14 Novo Nordisk A/S Modulatoren von protein tyrosin phosphatasen (ptpasen)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040167187A1 (en) * 2002-12-30 2004-08-26 Saunders Jeffrey O. Sulfhydantoins as phosphate isosteres
US7432292B2 (en) * 2002-12-30 2008-10-07 Vertex Pharmaceuticals Incorporated Sulfhydantoins as phosphate isosteres
US20040186151A1 (en) * 2003-02-12 2004-09-23 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
US20040192743A1 (en) * 2003-02-12 2004-09-30 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
US20050187277A1 (en) * 2004-02-12 2005-08-25 Mjalli Adnan M. Substituted azole derivatives, compositions, and methods of use
US20110092553A1 (en) * 2004-02-12 2011-04-21 Transtech Pharma, Inc. Substituted Azole Derivatives, Compositions, and Methods of Use
US20080293782A1 (en) * 2005-12-08 2008-11-27 David Barnes 1,1,3-Trioxo-1,2,5-Thiadiazolidines and Their Use as Ptp-Ases Inhibitors
US20100113331A1 (en) * 2006-01-30 2010-05-06 Transtech Pharma, Inc. Substituted Imidazole Derivatives, Compositions, and Methods of Use as PtPase Inhibitors
US7723369B2 (en) 2006-01-30 2010-05-25 Transtech Pharma, Inc. Substituted imidazole derivatives, compositions, and methods of use as PTPase inhibitors
US8404731B2 (en) 2006-01-30 2013-03-26 Transtech Pharma, Inc. Substituted imidazole derivatives, compositions, and methods of use as PTPase inhibitors
US20090181928A1 (en) * 2006-03-31 2009-07-16 Alan Neubert Organic compounds
US8084448B2 (en) * 2006-03-31 2011-12-27 Novartis Ag Organic compounds

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