Branched chain amino acid-dependent aminotransferase inhibitors and their use in treatment of diabetic retinopathy

A technology of alkylcycloalkyl and dimethylcyclohexyl, which is applied in the field of prevention and treatment of diabetic retinopathy, and can solve problems such as inactivity

Inactive Publication Date: 2004-10-13
WARNER LAMBERT CO LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, this pathway is inactive when glucose concentrations are normal

Method used

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  • Branched chain amino acid-dependent aminotransferase inhibitors and their use in treatment of diabetic retinopathy
  • Branched chain amino acid-dependent aminotransferase inhibitors and their use in treatment of diabetic retinopathy
  • Branched chain amino acid-dependent aminotransferase inhibitors and their use in treatment of diabetic retinopathy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0268] Example 1: trans-(1R,3R)(1-aminomethyl-3-methylcyclohexyl)acetic acid hydrochloride

[0269]

[0270]

[0271] (i) EtO 2 CCH 2 CN, NH 4 Ac, AcOH, toluene, 120°C

[0272] (ii) a. NaCN, EtOH (95%), H 2 O, 115°C, b.HCl (g)

[0273] (iii) EtOH, HCl (g), toluene

[0274] (iv) HCl, H 2 o

[0275] (v)H 2 , EtOH / NH 3 , Raney Ni, 30-50°C

[0276] (vi) HCl, H 2 O, 140°C

[0277] Step i: Ethyl 2-cyano-((R)-3-methylcyclohexylene)acetate

[0278] A mixture of 3-(R)-methylcyclohexanone (125mmol), ethyl cyanoacetate (124mmol), ammonium acetate (12.5mmol) and glacial acetic acid (24mmol) was refluxed in a Dean-Stark trap 24 hours. The mixture was cooled and washed with water. The aqueous washes were extracted with toluene. The toluene extract was combined with the original organic layer, dried over magnesium sulfate, and the solvent was evaporated. The oily crude product was purified by Kugelrohr d...

Embodiment 2

[0322] Example 2: (1-aminomethyl-2-methylcyclohexyl) acetic acid hydrochloride

[0323]

[0324] (i) EtO 2 CCH 2 CN, NH 4 Ac, AcOH, toluene, 120°C

[0325] (ii) a. NaCN, EtOH (95%), H 2 O, 115°C, b, HCl (g)

[0326] (iii) EtOH, HCl (g), toluene

[0327] (iv) HCl, H 2 o

[0328] (v) H 2 , EtOH / NH 3 , Raney Ni, 30-50°C

[0329] (vi) HCl, H 2 O, 140°C

[0330] Step i: Ethyl 2-cyano-(2-methylcyclohexylene)acetate

[0331] Following the general procedure (Example 1), step i, the reaction was carried out using (+ / -) 2-methylcyclohexanone (80 mmol), ethyl cyanoacetate (80 mmol), ammonium acetate (8 mmol) and glacial acetic acid (16 mmol) , a clear oil was obtained. Yield: 76%.

[0332] 1 HNMR (CDCl 3 )400MHzδ: 1.23 (3H, dd, J = 7, 10Hz), 1.35 (3H, t, J = 7Hz), 1.55-1.82 (5H, m), 1.93-2.05 (1H, m), 2.17 (1H, dt , J=5, 14Hz), 2.47 (1H, dt, J=5, 9Hz), 2.92-2.97 (1H, Brd, J=15Hz), 3.30-3.35 (1H, m), 3.81-3.86 (1H, Br d, J=15...

Embodiment 3

[0376] Example 3 (1-aminomethyl-3,3-dimethylcyclohexyl) acetic acid hydrochloride

[0377]

[0378]

[0379] i) CuI, MeLi, NH 4 Cl, NH 3 , (92%)

[0380] ii) NCCH 2 CO 2 Et, NH 4 OAc, AcOH, Toluene, (83%)

[0381] iii) NaCN, EtOH, H 2 O, (57%)

[0382] iv) HCl, EtOH, toluene, (93%)

[0383] v) H 2 , Raney Ni, EtOH, NH 3 , (84%)

[0384] vi) HCl, H 2 O, (64%)

[0385] Step i: 3,3-Dimethylcyclohexanone

[0386] The synthesis was carried out by the method described by Pelletier, S.W., Mody, N.V., J. Org. Chem., 1976.41, 1069.

[0387] A lithium dimethylcuprate solution was prepared by adding methyllithium (1.4M in diethyl ether, 77.25 mL, 2.45 mol) to copper(I) iodide (8.8 g, 0.046 mol) under argon atmosphere. The solution was cooled to 0° C., and 3-methylcyclohexen-1-one (5 mL, 0.044 mol) was added dropwise with stirring to form a dark yellow precipitate. The suspension was stirred at r...

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Abstract

The present invention is directed to a method for the prophylactic and therapeutic treatment of diabetic retinopathy. The method involves the administration of an inhibitor of formulae (I), (II) and (III) of the branch chain amino acid-dependent aminotransferase (BCAT) pathway to an animal, such as a mammal, in particular a human, in an amount sufficient to treat the retina for diabetic retinopathy prophylactically or therapeutically. The present invention is also directed to several novel inhibitors of formula (IV) of the BCAT pathway. In formulae (I-IV), n, m, X and R1-R13 have the meanings given in the description.

Description

Background of the invention [0001] In the United States, more than 14 million people have diabetes. All diabetics are at risk for developing retinal complications. However, patients with type 1 diabetes, ie, insulin-dependent diabetes, are at greater risk of severe vision loss than patients with type 2 diabetes, ie, non-insulin-dependent diabetes. [0002] Retinopathy is any non-inflammatory disease of the retina. Diabetic retinopathy is any disease of the retina associated with any type of diabetes. [0003] In people with diabetes, high blood sugar levels first cause an increase in growth factors in the patient's eyes. This pathological condition is known as the "prediabetic retinopathy stage" and, if not treated prophylactically, can lead to full diabetic retinopathy. [0004] Retinopathy will affect most people with diabetes to some degree throughout their lives. Today, retinopathy is the leading cause of blindness in Americans ages 20-74 and is projected to impair th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P1/04A61K31/19A61K31/194A61K31/195A61K31/27A61P3/10A61P9/10A61P25/00A61P25/08A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/02A61P27/06A61P29/00A61P43/00C07C55/28C07C59/11C07C59/62C07C229/10C07C229/14C07C229/18C07C229/22C07C229/28C07C229/34C07C233/08C07C233/47C07C271/22
CPCC07C229/28C07C59/11C07C2101/08C07C233/47C07C2101/02C07C2101/14C07C229/34C07C271/22C07C2101/04C07C2601/02C07C2601/04C07C2601/08C07C2601/14A61P1/04A61P25/00A61P25/08A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/02A61P27/06A61P29/00A61P43/00A61P9/10A61P3/10
Inventor J·S·布赖恩斯L-Y·胡S·M·赫特森K·F·兰欧E·列斯M·F·拉弗蒂T·R·赖德T-Z·苏D·F·威尔蒂D·J·伍斯特罗
Owner WARNER LAMBERT CO LLC
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