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3',3'-N-substituted macrolide LHRH antagonists

A technology of heterocycles and compounds, applied in the field of macrolide compounds, can solve the problems such as no reports of LHRH antagonists of macrolide compounds

Inactive Publication Date: 2001-07-11
ABBOTT LAB INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, there are no reports of macrolide compounds as LHRH antagonists in the literature

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0164] Example 13', 3'-N-didemethyl-3', 3'-N-dicyclopropylmethyl-11-deoxy-11-[carboxy-(4-chlorobenzene

[0165] Ethylamino)]-6-O-methylerythromycin A11,12-(cyclocarbamate)

[0166] 6-O-methylerythromycin A was purchased from Abbott Laboratories under the trade name BIAXIN, and protected at its 2'-position with a hydroxyl protecting group according to the method described in the literature. Step 1: 2'-O-Ac-4"-O-trimethylsilyl-6-O-methylerythromycin A (Compound 11, Reaction Scheme 3)

[0167] 2'-O-Ac-6-O-methylerythromycin A (45 g, 57 mmol) was dissolved in 450 mL of dichloromethane and cooled to 0°C in an ice / water bath. Pyridine (13.8 mL, 171 mmol) was added portionwise, followed by TMSCl (14.5 mL, 114 mmol) dropwise over 15 minutes. The reaction was stirred under the protection of a drying tube for 1 hour after which TLC (dichloromethane:methanol, 9:1) indicated complete conversion to the new, less polar material. with 500 mL of 0.5M NaH 2 PO 4 ...

Embodiment 23

[0180] Example 23', 3'-N-dor-3', 3'-N-dicyclobutyl-11-deoxy-11-[carboxy-(4-chlorophenethyl

[0181] Amino)]-6-O-methylerythromycin A11,12-(cyclocarbamate)

[0182] The title compound was prepared as described in Example 1 except that cyclobutanone was substituted for cyclopropanaldehyde. The product was purified by a silica gel column to obtain an amorphous solid:

[0183] R f =0.58(CHCl 3 :MeOH:NH 4 OH 94:5:1); IR(KBr)υ3440,2960,2925,1755,1730,1460,1380,1165,1105,1065,1050cm -1 ; 1HNMR (300MHz, CDCl 3 )δ7.45(d,J=2Hz,1H),7.34(d,J=8,Hz 1H),7.19(dd,J=8,2Hz,1H),4.92(d,J=5Hz,1H), 4.89(dd,J=11,2Hz,1H),4.40(d,J=7Hz,1H),4.02-3.99(m,1H),3.88-3.78(m,2H),3.72(d,J=10Hz, 1H), 3.69(s, 1H), 3.65(d, J=7, 1H), 3.47-3.44(m, 1H), 3.33(s, 3H), 3.31-3.26(series m, 2H), 3.12(q ,J=7Hz,2H)3.07(s,3H),3.05-2.84(series multimodal, 6H),2.65-2.61(m,1H),2.50(broad singlet, 1H),2.38(d,J=7Hz , 1H), 2.14-1.43 (series multimodal, 21H), 1.41 (s, 3H), 1.40 (s, 3H), 1.30 ...

Embodiment 33

[0184] Example 33', 3'-N-didemethyl-3', 3'-N-dicyclopropylmethyl-11-deoxy-11-[carboxy-(4-chlorobenzene

[0185] Ethylamino)]-6-O-methylerythromycin A11,12-(cyclocarbamate)

[0186] The title compound was prepared as described in Example 1 except that 4-chlorophenethylamine was substituted for 3,4-dichlorophenethylamine. The product is crystallized from acetonitrile / water:

[0187] R f =0.38(8%MeOH / DCM,0.1%NH 4 OH); IR(KBr)υ3440,2970,2940,1765,1735,1715,1490,1460,1420,1380,1330,1280,1235,1170,1130,1110,1095,1070,1055,1015,1000cm -1 ; 1 H NMR (300MHz, CDCl 3 )δ7.30-7.22 (series m, 4H), 4.96-4.92 (series m, 2H), 4.40 (d, J=67.1Hz, 1H), 4.04-3.97 (m, 1H), 3.87-3.80 (m, 2H),3.75-3.70(series m,3H),3.64(d,J=7.5Hz,1H),3.50-3.40(m,1H),3.34(s,3H),3.28-3.20(m,2H), 3.20-3.09(m,2H),3.07(s,3H),3.06-2.80(series m,5H),2.68-2.57(m,1H),2.54-2.43(m,1H),2.38(d,J= 15.3Hz,1H),2.10(d,J=10.2Hz,lH),2.08-1.98(series m,3H),1.97-1.82(series m,6H),1.80-1.74(m,2H),...

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Abstract

Disclosed are 3',3'-N-bisdesmethyl-3',3'-N-bis-substituted-6-O-methyl-11-deoxy-11,12 -cyclic carbamate erythromycin A derivatives of formula (I) which are antagonists of lutenizing hormone-releasing hormone (LHRH). Also disclosed are pharmaceutical compositions comprising the compounds, methods of using the compounds and the process of making the same.

Description

technical field [0001] The present invention relates to a class of macrolide compounds as luteinizing hormone-releasing hormone (LHRH) antagonists, pharmaceutical compositions containing these compounds, methods of use and preparation methods of these compounds. In particular, the present invention relates to 3',3'-N-didemethyl-3',3'-N-disubstituted-6-O-methyl-11-deoxy-11,12 as LHRH antagonists - Cyclic carbamate erythromycin A derivatives. Background of the invention [0002] Gonadotropins, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are required for ovulation, spermatogenesis, and sex steroid biosynthesis. A single hypothalamic hormone known as LHRH, gonadotropin-releasing hormone (GnRH), is responsible for regulating the secretion of FSH and LH in mammals. [0003] LHRH is a decapeptide with the following structure: [0004] pyro-Glu 1 -His 2 -Trp 3 -Ser 4 -Tyr 5 -Gly 6 -Leu 7 -Arg 8 -Pro 9 -Gly 10 -NH 2 Wher...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7042A61K31/7048A61P5/00A61P15/00A61P43/00C07H17/08
CPCC07H17/08A61P15/00A61P43/00A61P5/00A61K31/7048C07H1/00
Inventor D·R·绍尔F·哈维夫J·兰多尔夫N·A·莫尔特C·R·达尔顿M·布伦科M·A·卡明斯基B·W·克劳福德L·M·弗雷J·格雷尔
Owner ABBOTT LAB INC
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