Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase 4 and/or other PTPases with an Asp residue at position 48

A method of inhibiting at least one intracellular or membrane-associated PTPase that has aspartic acid (Asp) in position 48 using the numbering for PTP1B, the method comprising exposing said at least one PTPase in which inhibition is intended to an inhibitor compound which fits spatially into the active site and the vicinity thereof, said compound comprising the following features and moieties:

• I. a phosphate isostere which forms a salt bridge to the guanidinium group of arginine 221 and a hydrogen bond with a hydrogen atom donated by the backbone amide nitrogens of arginine 221 and glycine 220 such that the distance between the centroid of the phosphate isostere group and (I) the centroid of said guanidinium group ranges from 3.50–4.20 Å, (II) said arginine 221 backbone amide nitrogen ranges from 3.5–4.2 Å, and (III) said glycine 220 backbone amide nitrogen ranges from 2.7–3.5 Å;
• and
• II. (a) a carboxylic acid group or (b) a carboxylic acid isostere group selected from the following 5-membered heterocycles
• wherein said acid or said isostere group forms a salt bridge to the side chain amino group of lysine 120 wherein the distance between the centroid of said carboxylic acid or carboxylic acid isostere and the side chain nitrogen atom of said lysine 120 ranges from 3.4–4.1 Å;
• and
• III. a hydrophobic group that interacts with the aromatic ring of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.4–5.1 Å;
• and at least one of features IV through V:
• IV. a hydrophobic group that interacts with the aromatic ring of phenylalanine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said phenylalanine 182 ranges from 4.4–5.1 Å;
• and
• V. a hydrophobic group that interacts with the imidazole ring of histidine 182 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said histidine 182 ranges from 4.4–6.5 Å;
• and
• one or more of the following features VI–XXXVII:
• VI. an amino group which forms a salt bridge to the side chain carboxylic acid group of aspartic acid 48 such that the distance between the nitrogen atom of said amino group and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 3.4–4.1 Å;
• and
• VII. two oxygen atoms which form hydrogen bonds via a water molecule to the side chain carboxylic acid group of aspartic acid 48 such that the distance between each of the two oxygen atoms and the centroid of said water molecule ranges from 2.5–3.6 Å and that the distance between said water molecule and the centroid of said side chain carboxylic acid group of aspartic acid 48 ranges from 2.5–3.6 Å and that the distance between said two oxygen atoms ranges from 2.5–3.0 Å;
• and
• VIII. a hydrophobic group that interacts with the side chain methylene groups of tyrosine 46 such that the distance between the centroid of said hydrophobic group and the centroid of the methylene groups of said tyrosine 46 ranges from 4.4–5.1 Å;
• IX. a hydrophilic group that forms a hydrogen bond or forms a salt bridge with aspartic acid 181 such that the distance between the centroid of said hydrophilic group and the centroid of the carboxylic acid of said aspartic acid 181 ranges from 4.4–5.1 Å;
• X. a hydrophobic group that interacts with tyrosine 46 and the methylene side chain atoms of arginine 47 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic ring of said tyrosine 46 ranges from 4.7–5.2 Å and the centroid of the methylene side chain atoms of said arginine 47 ranges from 4.5–5.5 Å;
• XI. a hydrophilic group that forms a hydrogen bond with the one or more hydrogen atoms donated by the guanidinium group of arginine 47 such that the distance between the centroid of said hydrophilic group and the guanidinium group of said arginine 47 ranges from 2.7–3.5 Å;
• XII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of arginine 47 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said arginine 47 ranges from 2.7–4.0 Å;
• XIII. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide nitrogen of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said aspartic acid 48 ranges from 2.7–4.0 Å;
• XIV. a hydrophilic group that interacts with the backbone amide carbonyl group of asparagine 44 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said asparagine 44 ranges from 2.7–4.0 Å;
• XV. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 45 ranges from 2.7–4.0 Å;
• XVI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 45 ranges from 2.7–4.0 Å;
• XVII. a hydrophobic group that interacts with the side chain methylene groups of arginine 45 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 45 ranges from 4.4–5.1 Å;
• XVIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of arginine 45 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said arginine 45 ranges from 2.7–4.0 Å;
• XIX. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of tyrosine 46 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said tyrosine 46 ranges from 2.7–4.0 Å;
• XX. a hydrophilic group that forms a hydrogen bond with the side chain amino group of lysine 41 such that the distance between the centroid of said hydrophilic group and the amino group of said lysine 41 ranges from 2.7–4.0 Å;
• XXI. a hydrophobic group that interacts with the side chain methylene groups of lysine 41 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said lysine 41 ranges from 4.4–5.1 Å;
• XXII. a hydrophobic group that interacts with the side chain methylene groups of leucine 88 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said leucine 88 ranges from 4.4–5.1 Å;
• XXIII. a hydrophilic group that forms a hydrogen bond with the side chain hydroxy group of serine 118 such that the distance between the centroid of said hydrophilic group and the hydroxy group of said serine 118 ranges from 2.7–4.0 Å;
• XXIV. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of leucine 119 such that the distance between the centroid of said hydrophilic group and the amide carbonyl group of said leucine 119 ranges from 2.7–4.0 Å;
• XXV. a hydrophilic group that forms a hydrogen bond with the one of the hydrogen atoms donated by the side chain amide nitrogen of glutamine 262 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glutamine 262 ranges from 2.7–4.0 Å;
• XXVI. a hydrophilic group that forms a hydrogen bond with the hydrogen atom donated by the backbone amide group nitrogen of glycine 259 such that the distance between the centroid of said hydrophilic group and the amide nitrogen group of said glycine 259 ranges from 2.7–4.0 Å;
• XXVII. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the side chain guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
• XXVIII. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 254 ranges from 2.7–4.0 Å;
• XXIX. a hydrophobic group that interacts with the side chain methylene groups of arginine 254 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 254 ranges from 4.4–5.1 Å;
• XXX. a hydrophilic group that forms a hydrogen bond with one or more hydrogen atoms donated by the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
• XXXI. a hydrophilic group that forms a salt bridge with the guanidinium group of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the guanidinium group of said arginine 24 ranges from 2.7–4.0 Å;
• XXXII. a hydrophobic group that interacts with the side chain methylene groups of arginine 24 such that the distance between the centroid of said hydrophilic group and the centroid of the methylene groups of said arginine 24 ranges from 4.4–5.1 Å;
• XXXIII. a hydrophilic group that forms a hydrogen bond with the backbone amide carbonyl group of aspartic acid 48 such that the distance between the centroid of said hydrophilic group and the backbone amide carbonyl group of said aspartic acid 48 ranges from 2.7–3.5 Å;
• XXXIV. a hydrophobic group that interacts with the side chain atoms of methionine 258 such that the distance between the centroid of said hydrophobic group and the centroid of the side chain of said methionine 258 ranges from 4.5–6.2 Å;
• XXXV. a hydrophobic group that interacts with glycine 259 such that the distance between the centroid of said hydrophobic group and the centroid of the alpha-carbon atom of said glycine 259 ranges from 4.5–6.2 Å;
• XXXVI. a hydrophobic group that interacts with phenylalanine 52 such that the distance between the centroid of said hydrophobic group and the centroid of the aromatic group of said phenylalanine 52 ranges from 4.1–9.1 Å;
• or
• XXXVII. a hydrophobic group that interacts with methionine 258, glycine 259 and phenylalanine 52 being part of a hydrophobic pocket such that the distance between the centroid of said hydrophobic group and (i) the centroid of the side chain of said methionine 258 ranges from 4.1–7.2 Å, (ii) the centroid of said glycine 259 ranges from 4.7–7.7 Å, and (iii) the centroid of the side chain of said phenylalanine 52 ranges from 4.1–9.1 Å,
• wherein said compound is of the Formula 1
• wherein
• n is 0, 1 or 2, with the proviso that n is 1 or 2 when m is 0;
• m is 0, 1 or 2, with the proviso that m is 1 or 2 when n is 0;
• X is S, O, or NR8;
• Y is NR7, O, S, SO, or SO2;
• R1 is hydrogen, COOR3, or selected from the following 5-membered heterocycles:
• R2 is hydrogen, C1–C6alkyl, hydroxy, or NR9R10;
• R3 is hydrogen, C1–C6alkyl, arylC1–C6alkyl, C1–C6alkylcarbonyloxyC1–C6alkyl, or C1–C6alkylcarbonyloxyarylC1–C6alkyl;
• R4, R5 and R6 are independently hydrogen, trihalomethyl, C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, carboxy, carboxyC1–C6alkyl, C1–C6alkyloxy-carbonyl, aryloxycarbonyl, arylC1–C6alkyloxycarbonyl, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxy, arylC1–C6alkyloxy, arylC1–C6alkyloxyC1–C6alkyl, thio, C1–C6alkylthio, C1–C6alkylthioC1–C6alkyl, arylthio, arylC1–C6alkylthio, arylC1–C6alkylthioC1–C6alkyl, NR9R10, C1–C6alkylaminoC1–C6alkyl, arylC1–C6alkylaminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarbonylC1–C6alkyl, arylC1–C6alkylcarbonyl, arylC1–C6alkylcarbonylC1–C6alkyl, C1–C6alkylcarboxy, C1–C6alkylcarboxyC1–C6-alkyl, arylcarboxy, arylcarboxyC1–C6alkyl, arylC1–C6alkylcarboxy, arylC1–C6alkylcarboxyC1–C6alkyl, C1–C6alkylcarbonylamino, C1–C6alkylcarbonyl-aminoC1–C6alkyl, -carbonylNR7C1–C6alkylCOR13, arylC1–C6alkylcarbonyl-amino, arylC1–C6alkylcarbonylaminoC1–C6alkyl, CONR9R10, or C1–C6alkyl-CONR9R10 wherein the alkyl and aryl groups are optionally substituted and R13 is NR9R10, or C1–C6alkylNR9R10;
• R7 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkyloxocarbonyl, arylcarbonyl, aryloxocarbonyl, arylC1–C6alkylcarbonyl, arylC1–C6alkyloxocarbonyl, C1–C6alkylcarboxy, arylC1–C6alkylcarboxy, R9R10NcarbonylC1–C6alkyl wherein R9 and R0 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy;
• wherein the alkyl and aryl groups are optionally substituted;
• R8 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkyl-carboxy wherein the alkyl and aryl groups are optionally substituted;
• R9 and R10 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy wherein the alkyl and aryl groups are optionally substituted;
• or
• R9 and R10 are together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system can optionally be substituted with at least one C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, oxo, C1–C6alkyloxy, arylC1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, NR11R12 or C1–C6alkylamino-C1–C6alkyl, wherein R11 and R12 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy;
• wherein the alkyl and aryl groups are optionally substituted;
• or
• R9 and R10 are independently a saturated or partial saturated cyclic 5, 6 or 7 membered amine, imide or lactam;
• or a salt thereof with a pharmaceutically acceptable acid or a base, or any optical isomer or mixture of isomers thereof, or any tautomer thereof.