US 12,747,212 B2Granted

Pyridine derivatives as TMEM16A modulators for use in the treatment of respiratory conditions

AssigneeTMEM16A Limited

InventorsStephen Collingwood, Craig Buxton, Jonathan David Hargrave, Peter Ingram, Thomas Beauregard Schofield, Abdul Shaikh, Christopher Stimson

Life of this patent

Estimating the term…

Abstract

Compounds of general formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined herein are useful for treating respiratory disease and other diseases and conditions modulated by TMEM16A.

Claims14

Dependent claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
R1 is selected from methyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, ethynyl and CN;
or
R2 is selected from methyl and CH2OH;
R3 is selected from H and methyl;
or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic or oxygen-containing heterocyclic ring system, either of which is optionally substituted, in addition to the R1 group, with one or more substituents selected from OH, halo, C1-4 alkyl, C1-4 alkyl substituted with one or more OH substituents, and C1-4 haloalkyl;
or
when R2 and R3 together with the carbon atom to which they are attached form a 4- to 6-membered carbocyclic ring substituted, in addition to the R1 group, with OH, halo, methyl or CH2OH, R1 may also be H;
or
when R2 and R3 together with the carbon atom to which they are attached form a 4- to 6-membered carbocyclic ring, which is unsubstituted apart from the R1 group;
R1 may also be CH2OH;
or
R1, R2 and R3 together with the carbon atom to which they are attached combine to form a 5- to 8-membered bridged carbocyclic or heterocyclic ring system optionally substituted with one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 haloalkyl;
R4 is H or halo;
each of R5 and R7 is independently selected from H, halo, C1-3 alkyl and C1-3 haloalkyl;
R6 is selected from halo, CN and C1-4 alkyl optionally substituted with one or more substituents selected from halo and OH;
R8 is methyl or ethyl, either of which is optionally substituted with one or more halogen substituents;
R9 is OH, CH2OH or methyl or ethyl, either of which is optionally substituted with one or more halogen substituents;
or
R8 and R9 together with the carbon atom to which they are attached form either a 3- to 6-membered cycloalkyl or oxygen-containing heterocyclic ring optionally substituted, in addition to the R10 group, with one or more substituents selected from OH, F and CH2OH;
or an ethenyl group optionally substituted with one or two halogen substituents;
R10 is selected from H, CN, OH, cycloalkyl optionally substituted with OH, and C1-4 alkyl optionally substituted with one or more substituents selected from halo, OH and a 3- to 6-membered cycloalkyl or heterocyclic group, either of which is optionally substituted with OH;
or
R8, R9 and R10 together with the carbon atom to which they are attached form a 5- to 8-membered fused or bridged carbocyclic ring system optionally substituted with one or more substituents selected from OH, F and CH2OH;
provided that:
i. when R5 and R7 are H and R6 is H or F, R1, R2, R3, R8, R9 and R10 are not all methyl;
and
ii. when R2, R3, R8, R9 and R10 are all methyl, R5, R6 and R7 are not all H;
and
iii. when R1 is CN and R2 and R3 together with the carbon atom to which they are attached form a 3- to 10-membered oxygen-containing heterocyclic ring, R8, R9 and R10 are not all methyl;
and
iv. R9 and R10 are not both OH.

30 more elements

A compound selected from:

4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 1);
4-[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 1.1);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide (Compound 1.2);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyanoethyl)pyridine-2-carboxamide (Compound 1.3);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyanoethyl]pyridine-2-carboxamide (Compound 1.3a/b);
4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyanoethyl]pyridine-2-carboxamide (Compound 1.3 a/b);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 1.4);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 1.5);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 1.6);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 1.6 a/b);
4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 1.6 a/b);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 1.7);
4-[[2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl) phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2);
N-(1-Cyano-1-methyl-ethyl)-4-[[2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 2.1);
N-tert-Butyl-4-[[2-[4-(1-cyano-1-methyl-ethyl)-2-fluoro-5-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 2.2);
4-[[2-[4-(1-Cyano-1-methyl-ethyl)-2-fluoro-5-hydroxy-phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.3);
N-tert-Butyl-4-[2-[4-(1-cyanocyclopropyl)-2-fluoro-5-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 2.4);
N-(1-Cyano-1-methyl-ethyl)-4-[2-[4-(1,1-dimethyl-2-morpholino-ethyl)-2-fluoro-5-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 2.5);
4-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.6);
N-(1-Cyano-1-methyl-ethyl)-4-[[2-[2-fluoro-5-hydroxy-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 2.7);
4-[[2-[4-(1-Cyclopropyl-1-hydroxy-ethyl)-2-fluoro-5-hydroxy-phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.8);
4-[[2-[4-(4-Cyanotetrahydropyran-4-yl)-2-fluoro-5-hydroxy-phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.9);
4-[[2-[2-Fluoro-5-hydroxy-4-[2-(trifluoromethyl) oxetan-2-yl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.10);
4-[[2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-propyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.11);
4-[[2-[2-Fluoro-5-hydroxy-4-[(1S)-1-hydroxy-1-methyl-propyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.11 a/b);
4-[[2-[2-fluoro-5-hydroxy-4-[(1R)-1-hydroxy-1-methyl-propyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.11 a/b);
4-[[2-[5-Hydroxy-4-(1-hydroxy-1-methyl-ethyl)-2-methyl-phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.12);
4-[[2-[2-Fluoro-5-hydroxy-4-[1-(hydroxymethyl)cyclobutyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.13);
N-(1-Cyano-1-methyl-ethyl)-4-[[2-[2-fluoro-5-hydroxy-4-[2-(trifluoromethyl)oxetan-2-yl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 2.14);
4-[[2-[2-Fluoro-5-hydroxy-4-[4-(hydroxymethyl)tetrahydropyran-4-yl] phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.15);
4-[[2-[2-Fluoro-5-hydroxy-4-[1-(hydroxymethyl)cyclopropyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 2.16);
4-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)-5-fluoro-pyridine-2-carboxamide (Compound 3);
N-(1-Cyanocyclopropyl)-4-[[2-[2-deuterio-6-fluoro-3-hydroxy-4-[2,2,2-trideuterio-1,1-bis(trideuteriomethyl)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 4);
N-(1-Cyano-1-methyl-ethyl)-4-[2-[2-fluoro-5-hydroxy-4-(1-methylcyclo butyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5);
N-tert-Butyl-4-[[2-(4-tert-butyl-5-hydroxy-2-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 6);
N-tert-Butyl-4-[[2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 7);
4-[[2-(2-Fluoro-5-hydroxy-4-isopropenyl-phenyl)acetyl]amino]-N-[1-(trifluoromethyl) cyclopropyl]pyridine-2-carboxamide (Compound 7.1);
N-tert-Butyl-4-[[2-[2-fluoro-5-hydroxy-4-(1-methylcyclopropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 8);
N-(1-Cyanocyclopropyl)-4-[[2-[2-fluoro-5-hydroxy-4-[1-(trifluoromethyl) cyclopropyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 9);
4-[[2-(4-tert-Butyl-2-chloro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 10);
4-[[2-(4-tert-Butyl-2-chloro-5-hydroxy-phenyl)acetyl]amino]-N-[1-(trifluoromethyl) cyclopropyl]pyridine-2-carboxamide (Compound 10.1);
4-[[2-(4-tert-Butyl-2-chloro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl) pyridine-2-carboxamide (Compound 10.2);
4-[[2-[2-Fluoro-5-hydroxy-4-(3-hydroxy-1,1-dimethyl-propyl) phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 11);
N-(4-Cyanotetrahydropyran-4-yl)-4-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 12);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-[3-(trifluoromethyl)oxetan-3-yl]pyridine-2-carboxamide (Compound 12.1);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-[(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 12.2);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 12.3);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 12.4);
4-[[2-[2-Fluoro-5-hydroxy-4-(4-hydroxytetrahydropyran-4-yl) phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 13);
4-[[2-[2-Chloro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 14);
4-[[2-[5-Hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-2-methyl-phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 14.1);
N-(3,3-Difluoro-1-methyl-cyclobutyl)-4-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 15);
4-[[2-[2-Chloro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 15.1);
4-[[2-[2-Chloro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-(3,3-difluoro-1-methyl-cyclobutyl)pyridine-2-carboxamide (Compound 15.2);
4-[[2-[2-Chloro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl) phenyl]acetyl]amino]-N-[1-(difluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 15.3);
N-[1-(Difluoromethyl)cyclopropyl]-4-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 15.4);
N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 16);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 16.1);
N-(1-Cyano-1-methyl-ethyl)-4-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 16.2);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 16.3);
4-[[2-[2,6-Difluoro-3-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 16.4);
4-[[2-[2-Fluoro-5-hydroxy-4-[2,2,2-trifluoro-1-(hydroxymethyl)ethyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 17);
4-[[2-[2-Chloro-6-fluoro-3-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 18);
4-[[2-[2-Chloro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 19);
4-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 20);
4-[[2-[2-Fluoro-5-hydroxy-4-[(1S)-2-hydroxy-1-methyl-ethyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 20a/b);
4-[[2-[2-fluoro-5-hydroxy-4-[(1R)-2-hydroxy-1-methyl-ethyl]phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (Compound 20a/b);
and salts and solvates of the above.

65 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/581,504Filed 21 Jan 2022 · continuation
Priority: GB 191060724 Jul 2019
Published: US 2022/0235006 A128 Jul 2022
Granted: 29 Sep 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 213/81
Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals: amides; Imides
A61K 31/44
Having six-membered rings with one nitrogen as the only ring hetero atom: non condensed pyridines; Hydrogenated derivatives thereof
A61K 31/4433
Containing further heterocyclic ring systems: containing a six-membered ring with oxygen as a ring hetero atom
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…

Family

PCT/GB2020/051778Parent of this continuation · filed 24 Jul 2020
US 2022/0235006 A1Pre-grant publication · published 28 Jul 2022
US 12,747,212 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
R1 is selected from methyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, ethynyl and CN;
or
R2 is selected from methyl and CH2OH;
R3 is selected from H and methyl;
or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic or oxygen-containing heterocyclic ring system, either of which is optionally substituted, in addition to the R1 group, with one or more substituents selected from OH, halo, C1-4 alkyl, C1-4 alkyl substituted with one or more OH substituents, and C1-4 haloalkyl;
or
when R2 and R3 together with the carbon atom to which they are attached form a 4- to 6-membered carbocyclic ring substituted, in addition to the R1 group, with OH, halo, methyl or CH2OH, R1 may also be H;
or
when R2 and R3 together with the carbon atom to which they are attached form a 4- to 6-membered carbocyclic ring, which is unsubstituted apart from the R1 group;
R1 may also be CH2OH;
or
R1, R2 and R3 together with the carbon atom to which they are attached combine to form a 5- to 8-membered bridged carbocyclic or heterocyclic ring system optionally substituted with one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 haloalkyl;
R4 is H or halo;
each of R5 and R7 is independently selected from H, halo, C1-3 alkyl and C1-3 haloalkyl;
R6 is selected from halo, CN and C1-4 alkyl optionally substituted with one or more substituents selected from halo and OH;
R8 is methyl or ethyl, either of which is optionally substituted with one or more halogen substituents;
R9 is OH, CH2OH or methyl or ethyl, either of which is optionally substituted with one or more halogen substituents;
or
R8 and R9 together with the carbon atom to which they are attached form either a 3- to 6-membered cycloalkyl or oxygen-containing heterocyclic ring optionally substituted, in addition to the R10 group, with one or more substituents selected from OH, F and CH2OH;
or an ethenyl group optionally substituted with one or two halogen substituents;
R10 is selected from H, CN, OH, cycloalkyl optionally substituted with OH, and C1-4 alkyl optionally substituted with one or more substituents selected from halo, OH and a 3- to 6-membered cycloalkyl or heterocyclic group, either of which is optionally substituted with OH;
or
R8, R9 and R10 together with the carbon atom to which they are attached form a 5- to 8-membered fused or bridged carbocyclic ring system optionally substituted with one or more substituents selected from OH, F and CH2OH;
provided that:
i. when R5 and R7 are H and R6 is H or F, R1, R2, R3, R8, R9 and R10 are not all methyl;
and
ii. when R2, R3, R8, R9 and R10 are all methyl, R5, R6 and R7 are not all H;
and
iii. when R1 is CN and R2 and R3 together with the carbon atom to which they are attached form a 3- to 10-membered oxygen-containing heterocyclic ring, R8, R9 and R10 are not all methyl;
and
iv. R9 and R10 are not both OH.

30 more elements

Facts

Application

17/581,504Filed 21 Jan 2022 · continuation

Priority

GB 191060724 Jul 2019

Published

US 2022/0235006 A128 Jul 2022

Granted

29 Sep 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 213/81
Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals: amides; Imides
A61K 31/44
Having six-membered rings with one nitrogen as the only ring hetero atom: non condensed pyridines; Hydrogenated derivatives thereof
A61K 31/4433
Containing further heterocyclic ring systems: containing a six-membered ring with oxygen as a ring hetero atom
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…