Use of acetyl-coa carboxylase inhibitors for treating acne vulgaris

A technology of acetyl coenzyme and carboxylase, which is applied in the direction of medical preparations containing active ingredients, organic active ingredients, skin diseases, etc., and can solve problems such as dose limitation

Inactive Publication Date: 2016-04-27
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, isotretinoin causes serious mucocutaneous tolerance problems (dry skin, eyes, nasal passages, lips, etc.), which may limit doses if not properly managed with palliative medicine

Method used

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  • Use of acetyl-coa carboxylase inhibitors for treating acne vulgaris
  • Use of acetyl-coa carboxylase inhibitors for treating acne vulgaris
  • Use of acetyl-coa carboxylase inhibitors for treating acne vulgaris

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Inhibition of Sebum Production in Healthy Human Volunteers

[0031] Sebum production was evaluated in healthy volunteers treated with 200 mg BID of Example 1 or placebo (PBO). as by sebum meter (Courage+Khazaka Electronics Company, Cologne, Germany), the dose of Example 1 can reduce the sebum production (adjusted by PBO) in healthy volunteers by 49% (from baseline) ( Figure 4 ). Analyzes were used at baseline and at the end of the study The specific lipid class of the collected sebum demonstrated a 66% (PBO-adjusted) reduction in sebum triglycerides (the major lipid class of sebum) (Fig. 5). The amount of sebum free fatty acids and waxy esters (which are also dependent on DNL) was also reduced in Example 1 treated subjects (Figure 5). In contrast, free cholesterol (which is DNL independent) showed no change relative to PBO (data not shown). The amount of squalene (which is also DNL independent) showed a 2.6-fold increase relative to PBO. Since squalen...

Embodiment 2

[0298]

[0299] 1-Isopropyl-1’-(7-methoxy-2-naphthoyl)-4,6-dihydrospiro[indazole-5,4’-piperidin]-7(1H)-one

[0300] Triethylamine (304 mg, 3.00 mmol) was added to 7-methoxy-2-naphthoic acid (202 mg, 1.00 mmol) and 1-isopropyl-4 in dichloromethane (15 mL), 6-Dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one (329 mg, 1.05 mmol) solution, then add 1-hydroxybenzotriazole (149 mg, 1.10 Millimoles). The reaction mixture was stirred at room temperature for 15 minutes, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (211 mg, 1.10 mmol) was added and the reaction was stirred for 15 hours. Then, the mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Analysis by flash chromatography (20-100% 1:9 methanol / heptane in ethyl acetate, 24 g Gold column) the resulting residue was purified to yield 342 mg (79%) of 1-isopropyl-1'-(7-m...

Embodiment 3

[0303]

[0304] 1’-(2-Aminoquinoline-7-carbonyl)-1-isopropyl-4,6-dihydrospiro[indazole-5,4’-piperidin]-7(1H)-one

[0305]

[0306] 1'-(2-(tert-butylamino)quinoline-7-carbonyl)-1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidine]-7(1H) -ketone

[0307] The title compound was prepared by a method similar to that described in Example 25, Step 1 of US2012 / 0270893 (incorporated herein by reference).

[0308] +APCI(M+H)474.6; 1 HNMR (400MHz, CDCl 3 ,δ):7.72(d,J=8.8Hz,1H),7.64(s,1H),7.55(d,J=8.2Hz,1H),7.36(s,1H),7.16(dd,J=8.1, 1.3Hz, 1H), 6.59(d, J=9.2Hz, 1H), 5.36(quin, J=6.6Hz, 1H), 3.31-3.96(m, 4H), 2.79(s, 2H), 2.58(s, 2H), 1.55-1.75 (m, 4H), 1.52 (s, 9H), 1.44 (d, J=6.4Hz, 6H).

[0309]

[0310] 1'-[(2-Aminoquinolin-7-yl)carbonyl]-1-isopropyl-1,4-dihydrospiro[indazole-5,4'-piperidin]-7(6H)-one Trifluoroacetate

[0311] Add trifluoroacetic acid (0.90 mL, 12 mmol) to 1'-(2-(tert-butylamino)quinoline-7-carbonyl)-1-isopropyl-4,6-dihydrospiro[indazole- 5,4'-piperid...

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Abstract

The present invention relates to methods of treating and / or preventing acne in patients comprising the step of administering to patients in need of such treatment a therapeutically effective amount of an ACC inhibitor or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to methods of treating and / or preventing the progression of acne (acne) using inhibitors of acetyl-CoA carboxylase (ACC) or pharmaceutical compositions containing such inhibitors. Background technique [0002] Acne consists of a spectrum of skin lesions, including comedones, inflammatory papules, pustules, nodules, and cysts. The disease is classified as mild, moderate, or severe based on the severity of the injury and the anatomical distribution of the injury. Onset of the disease usually occurs during puberty, as increased levels of androgens trigger increased sebum production. About 90% of adolescents are affected by acne, and 15% seek medical attention; furthermore, the disease continues to be prevalent in 23-35% of young adults (18-28 years). Biologically, acne is considered an inflammatory disease of the pilosebaceous duct with several distinctive features, including: (a) excessive sebum production; (b) abnormal ke...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4709A61P17/10
CPCA61K31/4709A61P17/08A61P17/10A61P43/00
Inventor W·P·埃斯勒G·E·索南伯格
Owner PFIZER INC
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