Substituted cathechols as inhibitors of IL-4 and IL-5 for the treatment of bronchial asthma

Patent metadata

Field	Value
Publication number	US-9302967-B2
Application number	US-201214110869-A
Country	US
Kind code	B2
Filing date	Apr 11, 2012
Priority date	Apr 11, 2011
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The present invention relates to compounds of general formula 1 for the treatment of bronchial asthma by inhibition of IL-4 or IL-5 pathway inhibition. The present invention also relates to the use of compound of general formula 1 for the treatment of bronchial by inhibition of IL-4 or IL-5 pathway. The present invention also relates to the method of treating asthma by inhibition of IL-4 or IL-5 pathway by administration of compound or said composition through oral, intranasal, route or by inhalation to a mammal in need thereof. Compound of general formula 1 may be used for reducing perivascular and peribronchial inflammation.

First claim

The invention claimed is:

1. A method for the treatment of a mammal suffering from bronchial asthma consisting essentially of administering to the mammal in need thereof a therapeutically effective amount of:
i. one or more compounds general formula 1 having the structure:

wherein R 1 =—H or —COCH 3 , R 2 =—H or —COCH 3 , or wherein R 1 and R 2 are covalently coupled to —CH 2 — comprising a five member ring with the structure:

wherein R 4 =—H or —CH 2 —CH═CH 2 or —CH 2 —CH 2 —CH 3
wherein R 5 =—H or —CH 2 —CH═CH 2 ; and
wherein R 6 =—H or —CH 2 —CH═CH 2 ;

ii. one or more compounds with formula I having the structure:

wherein R 1 =—H or —COCH 3 , R 2 =—H or —COCH 3 , or wherein R 1 and R 2 are covalently coupled to —CH 2 — comprising a five member ring with the structure:

wherein R 3 =—H;
wherein R 4 =—CH═CH 2 or —CH 2 —CH 3 or —CH═NOH or —CN or —CH═NOAc or —CH═CH—COOEt;
wherein R 5 =—H or —CH 2 —CH═CH 2 ;
wherein R 6 =—H or —CH 2 —CH═CH 2
wherein R=—H or —CH 3 ; and
wherein R 8 =—H or —CH 3 ;

iii. one or more compounds with formula II having the structure:

wherein R 1 =—H or —COCH 3 , R 2 =—H or —COCH 3 , or wherein R 1 and R 2 are covalently coupled to —CH 2 — comprising a five member ring with the structure:

wherein R 3 =—CH═CH 2
wherein R 4 =—H or —CH 2 —CH═CH 2 or —CH 2 —CH 2 —CH 3 ;
wherein R 5 =—H or —CH 2 —CH═CH 2 ;
wherein R 6 =—H or —CH 2 —CH═CH 2 ;
wherein R 7 =—H; and
wherein R 8 =—H; and

wherein the bronchial asthma is treated by IL-4 or IL-5 pathway inhibition.

2. The method of claim 1 , wherein said one or more compounds comprises:
(1) 4-allyl-benzene-1,2-diol (hydroxychavicol),
(2) 4,5-diallylbenzene-1,2-diol,
(3) 3,4-diallylbenzene-1,2-diol,
(4) 4-allyl-5-propylbenzene-1,2-diol,
(5) 4,5-diallyl-1,2-phenylene diacetate,
(6) 3,4-diallyl-1,2-phenylene diacetate,
(7) 4-allyl-1,2-phenylene diacetate,
(8) 4-allyl-5-propyl-1,2-phenylene diacetate,
(9) 2-(3,4-dihydroxyphenyl)-2-methylpropanal oxime,
(10) 2-(3,4-dihydroxyphenyl)-2-methylpropanenitrile,
(11) 4-(2-cyanopropan-2-yl)-1,2-phenylene diacetate,
(12) 4-(1-(acetoxyimino)-2-methylpropan-2-yl)-1,2-phenylene diacetate,
(13) (E)-ethyl 4-(3,4-dihydroxyphenyl)-4-methylpent-2-enoate,
(14) 5-(2-methylbut-3-en-2-yl)benzo[d][1,3]dioxole,
(15) (E)-4-(5-ethoxy-2-methyl-5-oxopent-3-en-2-yl)-1,2-phenylene diacetate,
(16) 3-allyl-benzene-1,2-diol,
(17) 3-allyl-4-propylbenzene-1,2-diol,
(18) 3,4-diallyl-5-propylbenzene-1,2-diol,
(19) 3-allyl-1,2-phenylene diacetate,
(20) 3-allyl-4-propyl-1,2-phenylene diacetate; or
(21) 3,4-diallyl-5-propyl-1,2-phenylene diacetate.

3. The method of claim 1 , wherein the compound is administered through oral, intranasal, route or by inhalation to said mammal.

4. The method of claim 1 , wherein said compound increases PC 200 Mch in the range of 0.1 mg to 10.0 mg per kg body weight.

5. The method of claim 1 , wherein the concentration of the compound used for Inhibition of stimulation-induced IL-4 (IC 50 ) is in the range of 5 to 30 μM.

6. The method of claim 1 , wherein the concentration of the compound used for Inhibition of stimulation-induced IL-5 (IC 50 ) is in the range of 4.5 to 35 μM.

7. The method of claim 1 , wherein the concentration of the compound used for reducing immunoglobulin E (IgE) is in the range of 0.1 mg to 10.0 mg per kg body weight.

8. The method of claim 1 , wherein the concentration of the compound used for reducing lung inflammation is in the range of 5.0 mg to 10.0 mg per kg body weight.

9. The method of claim 1 , wherein the concentration of the compound used for reducing perivascular and peribronchial inflammation is in the range of 5.0 mg to 10.0 mg per kg body weight.

10. The method of claim 3 , wherein said compound is administered orally.

11. The method of claim 3 , wherein said oral administration comprises capsule, syrup, powder or granules.

12. The method of claim 1 , wherein said compound of is administered at a dosage level between 0.1 mg to 10.0 mg per kg body weight twice a day for 6 months.

Assignees

• Bandyopadhyay Santu
• Ghosh Balaram
• Jaisankar Parasuraman
• Pal Bikas Chandra
• Roy Siddhartha
• Paul Bholanath
• Ram Arjun
• Mabalirajan Ulaganathan
• Ali Nahid
• Bandopadhyay Arun
• Konar Aditya
• Chakraborty Jayashree Bagchi
• Mukherjee Indrani Choudhury
• Chaudhuri Jaydeep
• Mahato Sanjit Kumar
• Manna Anirban
• Sinha Roma
• Bhattacharya Pradyot
• Vinayagam Jayaraman
• Jana Deba Prasad
• Chowdhury Sushovan
• Council Scient Ind Res

Inventors

• Bandyopadhyay Santu
• Ghosh Balaram
• Jaisankar Parasuraman
• Pal Bikas Chandra
• Roy Siddhartha
• Paul Bholanath
• Ram Arjun
• Mabalirajan Ulaganathan
• Ali Nahid
• Bandopadhyay Arun
• Konar Aditya
• Chakraborty Jayashree Bagchi
• Mukherjee Indrani Choudhury
• Chaudhuri Jaydeep
• Mahato Sanjit Kumar
• Manna Anirban
• Sinha Roma
• Bhattacharya Pradyot
• Vinayagam Jayaraman
• Jana Deba Prasad
• Chowdhury Sushovan

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61K31/215

  of carboxylic acids · CPC title

• C07C251/40

  to carbon atoms of an unsaturated carbon skeleton · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• C07D317/50

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring · CPC title