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US 7,622,593 B2Granted
Human protein tyrosine phosphatase inhibitors and methods of use
AssigneeThe Procter & Gamble Company
InventorsJeffrey Lyle Gray, Kande K. D. Amarasinghe, Cynthia Monesa Clark, Ryan Matthew Nichols, Matthew B. Maier
Life of this patent
Estimating the term…
Abstract
The present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors thereby regulating angiogenesis. The present disclosure further relates to compositions comprising said human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.
Claims49
A compound of the formula:
- wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
- said substitutions are independently chosen from one or more C1-C6 linear- or branched alkyl, or C3-C6 cyclic alkyl, halogen, hydroxy, OCH3, CF3, N(R12)2 or cyano units;
- R12 is independently hydrogen or C1-C4 linear or branched alkyl;
- R6 is a unit chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- R1 is chosen from:
- i) hydrogen;
- ii) C1-C6 linear or branched alkyl;
- iii) substituted or unsubstituted phenyl;
- or
- iv) substituted or unsubstituted benzyl;
- R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R3 is hydrogen or C1-C4 linear or branched alkyl;
- or a pharmaceutically acceptable salt thereof.
26 more elements
A compound of the formula:
- wherein R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
9 more elements
A compound of the formula:
- wherein R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R6 is chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl.
7 more elements
A compound of the formula:
- wherein R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
9 more elements
A compound of the formula:
- wherein R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R6 is chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl.
7 more elements
A compound of the formula:
- wherein R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
9 more elements
A compound of the formula:
- wherein R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R6 is chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or a pharmaceutically acceptable salt thereof.
8 more elements
A compound chosen from;
- 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(R)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
- {1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methyl carbamic acid tert-butyl ester;
- {(S)-2-Phenyl-1-[1-(2-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoyl]ethyl}carbamic acid tert-butyl ester
- 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(thiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-propylthiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[4-(2,2-Difluorocyclopropyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(methoxy-methyl)thiazol-2-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(5-phenylthiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[4-(3,4-Dimethylphenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Ethoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid;
- 4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(2-methylthiazole-4-yl)thiazole-4-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-pyrazine-2-yl)thiazole-4-yl}phenylsulfamic acid;
- and
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamic acid.
41 more elements
A compound chosen from:
- 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid;
- 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamic acid;
- 4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
- (S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamic acid;
- (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonylamino)acetamido]ethyl}phenyl-sulfamic acid;
- 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanamido]-ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
- 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentan-amido]ethyl}phenylsulfamic acid;
- 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid;
- and
- 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid.
9 more elements
A compound of the formula:
- wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
- said substitutions are independently chosen from one or more C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl, halogen, hydroxyl, or cyano units;
- R6 is a unit chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy.
17 more elements
A compound chosen from:
- [1-(S)-(Phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acid tert-butyl ester;
- (S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- (S)-4-(2-(4-Ethylthiazole-2-yl)-2-pivalamideoethyl)phenylsulfamic acid;
- (S)—N-(1-(4-Hydroxymethyl)thiazole-2-yl)-2pivalamidoethyl)phenylsulfamic acid;
- (S)-4-(2-(4-Ethoxycarbonyl)thiazole-2-yl)-2-pivalamideoethyl)phenylsulfamic acid;
- (S)-4-(2-(4-Phenylthiazole-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- 4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- N—((S)-1-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(4-nitrophenyl)ethyl)pivalamide;
- 4-((S)-2-(4-(3-methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- 4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamic acid;
- (S)-4-(2-(4-benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- (S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsulfamic acid;
- (S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- 4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- (S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- (S)-4-(2-(4-(4-Biphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;
- (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-propylthiazol-2-yl)ethyl)-phenyl sulfamic acid;
- (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-tert-butylthiazol-2-yl)ethyl)-phenyl sulfamic acid;
- and
- (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid.
17 more elements
A pharmaceutical composition comprising:
- A) one or more compounds of the formula:
- wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
- said substitutions are independently chosen from one or more C1-C6 linear, or branched alkyl, or C3-C6 cyclic alkyl, halogen, hydroxyl, or cyano units;
- R6 is a unit chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl;
- R1 is chosen from:
- i) hydrogen;
- ii) C1-C6 linear or branched alkyl;
- iii) substituted or unsubstituted phenyl;
- or
- iv) substituted or unsubstituted benzyl;
- R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R3 is hydrogen or C1-C4 linear or branched alkyl;
- or a pharmaceutically acceptable salt thereof, and
- B) one or more excipients or carriers.
27 more elements
A compound of the formula:
- wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
- R2 is chosen from:
- i) C1-C6 linear or branched alkyl;
- or
- ii) C1-C6 linear or branched alkoxy;
- R4 and R5 are each independently chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- iv) substituted or unsubstituted heteroaryl;
- or
- R4 and R5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
- R6 is a unit chosen from:
- i) hydrogen;
- ii) substituted or unsubstituted C1-C6 linear or branched alkyl, or C3-C6 cyclic alkyl;
- iii) substituted or unsubstituted phenyl;
- and
- iv) substituted or unsubstituted heteroaryl.
15 more elements
Dependencies are inferred from the claim text.