GB2612007A - Compounds - Google Patents
Compounds Download PDFInfo
- Publication number
- GB2612007A GB2612007A GB2108497.5A GB202108497A GB2612007A GB 2612007 A GB2612007 A GB 2612007A GB 202108497 A GB202108497 A GB 202108497A GB 2612007 A GB2612007 A GB 2612007A
- Authority
- GB
- United Kingdom
- Prior art keywords
- fused
- heterocycle
- carbocycle
- compound
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 239000002753 trypsin inhibitor Substances 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 6
- 239000001257 hydrogen Substances 0.000 claims abstract 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 4
- 230000028327 secretion Effects 0.000 claims abstract 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000007812 deficiency Effects 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 10
- 201000010099 disease Diseases 0.000 claims 5
- 208000035475 disorder Diseases 0.000 claims 5
- 239000000411 inducer Substances 0.000 claims 2
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 150000003839 salts Chemical group 0.000 claims 1
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 239000012039 electrophile Substances 0.000 description 23
- 150000001408 amides Chemical class 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010931 ester hydrolysis Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 101100327840 Arabidopsis thaliana CHLI1 gene Proteins 0.000 description 1
- 102100035861 Cytosolic 5'-nucleotidase 1A Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101000802744 Homo sapiens Cytosolic 5'-nucleotidase 1A Proteins 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to compounds of formula (1) where R1, R2, R3, R4, R5, R6 and R7 are independently hydrogen or optionally substituted C1-C6 alkyl groups; and/or R1 and R2 may be fused to form a heterocycle; and/or R3 and R4 may be fused to form a carbocycle; and/or R3 and R5 may be fused to form a carbocycle or a heterocycle; and/or R4 and R may be fused to form a carbocycle or a heterocycle; and/or R6 and R7 may be fused to form a carbocycle or heterocycle; X may be independently N or CH and when CH it may be optionally substituted; and/or Y may be N or CH provided that when R3 and R4 are both hydrogen, at least one X must be N; and their potential use, for example in the treatment of a1-antitrypsin deficiency (AATD) These compounds are also stated as potentially inducing Z a1-antitrypsin (Z A1AT) secretion. Compounds of formulae (2) and (3) as defined herein are also described.
Description
Compounds The present application relates to new compounds with potential use, for example in the treatment of al-antitrypsin deficiency (AATD).
According to the present invention, there is provided a compound, pharmaceutical composition, medical use and method of treatment as defined in the appended claims.
Unless otherwise defined, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which this invention belongs.
Similarly, all the publications, patent applications, all the patents and all other references mentioned here are incorporated by way of reference in their entirety (where legally permissible).
Particular aspects, examples and embodiments of the present invention are described below.
Scheme 1 Active compounds can be made directly using an amide electrophile (Step 4) or indirectly via ester hydrolysis and then amidation (Steps 1, 2 and 3) (Scheme 1). Those skilled in the art may select amines with a range of suitable RI and R2 groups. Suitable RH groups include CH3, CH2CH3, C(CH3)3.
Suitable 122 and R2 groups include H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2Ph. Herein DMF means dimethylformamide and CDI means carbonyldiimidazole. OR9 R9 01R9
BK-X N"
R-R9 R9
hydrolysis Step 2 e.g. using CF3CO2H or HCI, H20 Step 1 base, solvent e.g. Cs2CO3, DMF
I
L YH
Step 4 base, solvent e.g. Cs2CO3, DMF R1sN-R2 0 R1 amide coupling reagent N-R2 e.g. CD! Step 3
OH
Scheme 1.
Electrophiles to be used in Step 1 of Scheme 1 and their resulting amides formed after Steps 2 and 3 are shown in Table 1. Electrophiles to be used in Step 4 of Scheme 1 and their resulting amides formed directly are shown in Table 2.
Table 1. Structure of step 1 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound Step 1 electrophile Reference for synthesis of electrophile Biologically active compound Br 01110 0 0 ".. Synlett 2014, 25, 2485-2487 11101 D01:10.1055/s-0034-1379005 0 Br 0 0 0,... Synlett 2014, 25, 2485-2487 101 D 01:10.1055/s-0034-1379005 0 Br 0 0 0". W02008127364A2 0 IP Br 0 0 0.... W02003016316A1 0 CI ilio di --, 01 N 0 Br 00 F 0 0 -.. W02003016316A1 1101 11\1,, Br IP F 0 0"." W02011008572A2 0 IP F 0 Br------, 0 W02019182938A1 0 Br"----"--C-- W02019182938A1 NY I N --"(0--. N.-) N ----' N 0 0 --"t<,*-, W02019182938A1 ----, , Br."_."---..I NO., I 0 /Th....N., N W02017018803A1 _1 hlIN I Br N-7 N---- N...., N....-' O., 0 N W02017018803A1 0 "-----,....... ,...",.. Br 1 ;I N° ;Br."-----r-zs W02017018803A1 N N,N-5-..."(0---. _1 0 N..,-2' N..N---I --- 0,, W02017018803A1 0 Rip J-1 W02017027343A1 0 H. 8, CN I 0 lb IS o --. 0 0,w5D VHI ---S.'0, W02017027343A1 0 - 2,0 Parent alcohol: US20070155738A1 ill --:SO t th 0 WI o, Meane sulfonate according to the method for chiral secondary alcohols: Table 2 Structure of step 4 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound Step 4 electrophile Reference for synthesis of electrophile Biologically active compound B r lb F 0 H N...... W02018194181A1 10 0 kis.. ;Br F 110 0 1 W02018115591A1 110 0 N --.. ;Scheme 2 Active compounds can be made directly using an amide electrophile (Scheme 2, Step 4) or indirectly via ester hydrolysis and then amidation (Scheme 2, Steps 1, 2 and 3). Those skilled in the art may select amines with a range of suitable RI and R2 groups. Suitable Re groups include CH3, CH2CH3, C(CH3)3. Suitable RI and R2 groups include H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2Ph. ;base, solvent e.g. Cs2CO3, DMF ;NH OR8 ;hydrolysis StepStep 2 e.g. using CF3CO2H or HCI, H20 Ri R2 I\I" 0 A-4 amide coupling reagent I "JNIza)--4 N-R2 e.g. CM -z OH Step 3 Scheme 2. ;Electrophiles to be used in Step 1 of Scheme 2 and their resulting amides formed after Steps 2 and 3 are shown in Table 3. ;Table 3 Structure of step 1 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound Step 1 electrophile Reference for synthesis of electrophile Biologically active compound Br N 0 W02016177760A1 N/ Br \ . 10 0 N' 9 )-\ N 0 N/ Br 0 W02010020556A1 0 N N/ 0 0 W02013128421A1 N-B / / 0 0 N/ Br I N-N 0-N 0 W0201002 0556A1 ;B / 0 0 0 ;Br, N 0 ;I S N-/ ;0 W02017136727A2 0 Br 1 S 0 ;N N-N / ;I ;S 0 W01998054180A1 r / 0-\ / N-/ 0 0 Br"----.'"f---S____< I 0 N-0 0--\\ N 1 M N-7 N-0 N-/ 0 0-N 0- 0 / W02016054971A1 0 N-5J 0-N N-/ 0 W02006040568A1 W02006040568A1 0 / N-21 /N-Nj N-/ 0 N-N 0- 0 Br----yk\74 I W02006040568A1 0 \ N.C) NMI N-\ / Scheme 3 Active compounds can be made directly using an amide electrophile (Step 4) or indirectly via ester hydrolysis and then amidation (Steps 1, 2 and 3) (Scheme 2). Those skilled in the art may select amines with a range of suitable RI and R2 groups. Suitable R8 groups include CH3, CH2CH3, C(CF13)3. ;Suitable RI-and R2 groups include H, CH3, CH2CF13, CH(CH42, C(CH43, CH2Ph. ;Step 1 Brx_ Cy OR8 base, solvent e.g. Cs2003, DMF R1 R2 amide coupling reagent e.g. CH Step 3 hydrolysis StepStep 2 e.g. using CF3CO2H or HCI, H20 Scheme 3. ;Alternative electrophiles to be used in Step 1 of Scheme 3 and their resulting amides formed after Steps 2 and 3 are shown in Table 4. ;Table 4 Structure of step 1 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound Step 1 electrophile Reference for synthesis of electrophile Biologically active compound 0"0 0-, W02016054971A1 I 1.,o N....,. 0 0 ;0 W02015166373A1 0 I t-j(0- I^1*1-M---/ 0 W02014037498A2 0 Br 0", Bioorganic & Medicinal Chemistry, 2009, 17, 242-250 D01:10.1016/413mc.2008.11.015 II I 0 N ---...
Br 0 Eur J Med Chem. 2011, 46, 5728- CN 0 DOI:10.1016/j.ejmech.2011.06.0 23 Eur J Med Chem. 2011, 46, 5728-35 DOI:10.1016/j.ejmech.2011.06.0 23 CN 1
N---
Claims (13)
- Claims 1. A compound of fonnula (1) N. (1) where RI, R2, R3, 124, Rs. R6 and R7 are independently hydrogen or optionally substituted CI-C6 alkyl groups; and/or RI and R2 may be fused to form a heterocycle; and/or R3 and R4 may be fused to form a carbocycle; and/or 123 and Rs may be fused to form a carbocycle or a heterocycle; and/or R4 and Rs may be fused to form a carbocycle or a heterocycle; and/or R6 and R7 may be fused to form a carbocycle or heterocycle; X may be independently N or CH and when CH it may be optionally substituted; and/or Y may be N or CH provided that when R3 and R4 are both hydrogen, at least one X must be N.
- 2. A compound of formula (2) (2) where RI, R2, Rs, 124, R6 and R7 are independently hydrogen or optionally substituted CI-C6 alkyl groups; and/or RI and R2 may be fused to form a heterocycle; and/or R3 and R1 may be fused to form a carbocycle; and/or R6 and R7 may be fused to form a carbocycle or heterocycle; Z may be independently N, NH, S. 0 or CH and when CH or NH it may be optionally substituted; and/or Y may be N or CH.
- 3. A compound of formula (3) 0 R3 0 1...R4A 1 N Cy N R7 Y (3) where R2, R3, R4, R6 and R7 are independently hydrogen or optionally substituted CI-Co alkyl groups; and/or RI and R7 may be fused to form a heterocycle; and/or R3 and R4 may be fused to form a carbocycle; and/or R6 and R7 may be fused to form a a carbocyle or heterocycle; Cy is an aliphatic carbocycle; Y may be N or CH.
- 4. The compound according to claims 1, 2 or 3 in a pharmaceutically acceptable salt form or crystalline form.
- 5. A pharmaceutical composition comprising a compound according to any of claims 1, 2, 3 or 4 and a pharmaceutically or therapeutically acceptable excipient or carrier.
- 6. Use of a compound according to any of claims 1, 2, 3 or 4 in the manufacture of a medicament for the treatment of a disease or disorder.
- 7. The compound according to any of claims 1, 2, 3 or 4 for use in the treatment of a disease or disorder.
- 8. The compound according to any of claims 1, 2, 3 or 4 for use as an inducer of Z al-Antitrypsin (Z A1AT) secretion.
- 9. A method of treating a disease or disorder, comprising the step of administering a compound according to any of claims 1, 2, 3 or 4, or a pharmaceutical composition according to claim 5, to a patient in need of same.
- 10. Use of a compound according to any of claims 1, 2, 3 or 4 in the treatment of a disease or disorder.
- 11. The use according to claim 10 as an inducer of Z al-Antitrypsin (Z AlAT) secretion.
- 12. The use according to either of claim 10 or claim 11 wherein the use is in vitro.
- 13. The use according to claim 6, the compound for use according to claim 7, the method of treatment according to claim 9, or the use according to claim 10, wherein the disease or disorder is al-antitrypsin deficiency (AATD).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2108497.5A GB2612007A (en) | 2021-06-15 | 2021-06-15 | Compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2108497.5A GB2612007A (en) | 2021-06-15 | 2021-06-15 | Compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB202108497D0 GB202108497D0 (en) | 2021-07-28 |
| GB2612007A true GB2612007A (en) | 2023-04-26 |
Family
ID=76954597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2108497.5A Withdrawn GB2612007A (en) | 2021-06-15 | 2021-06-15 | Compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2612007A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113227057A (en) * | 2018-12-14 | 2021-08-06 | Z 因子有限公司 | Compounds and their use for the treatment of alpha 1-antitrypsin deficiency |
-
2021
- 2021-06-15 GB GB2108497.5A patent/GB2612007A/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113227057A (en) * | 2018-12-14 | 2021-08-06 | Z 因子有限公司 | Compounds and their use for the treatment of alpha 1-antitrypsin deficiency |
Also Published As
| Publication number | Publication date |
|---|---|
| GB202108497D0 (en) | 2021-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |