WO2022263817A1 - Compounds and their use for the treatment of alpha1-antitrypsin deficiency - Google Patents
Compounds and their use for the treatment of alpha1-antitrypsin deficiency Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 35
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 title abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 24
- 201000010099 disease Diseases 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 7
- 230000028327 secretion Effects 0.000 claims description 7
- 239000000411 inducer Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000003839 salts Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical group [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 102100022712 Alpha-1-antitrypsin Human genes 0.000 claims 3
- 101000823116 Homo sapiens Alpha-1-antitrypsin Proteins 0.000 claims 3
- 150000001805 chlorine compounds Chemical group 0.000 claims 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 5
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- QIDIKMICSNJEOW-MRVPVSSYSA-N OC([C@H](CCC1)CN1S(C1=C(C(F)(F)F)C(Cl)=CC=C1)(=O)=O)=O Chemical compound OC([C@H](CCC1)CN1S(C1=C(C(F)(F)F)C(Cl)=CC=C1)(=O)=O)=O QIDIKMICSNJEOW-MRVPVSSYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002753 trypsin inhibitor Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108010028275 Leukocyte Elastase Proteins 0.000 description 2
- 102000016799 Leukocyte elastase Human genes 0.000 description 2
- QIDIKMICSNJEOW-QMMMGPOBSA-N OC([C@@H](CCC1)CN1S(C1=C(C(F)(F)F)C(Cl)=CC=C1)(=O)=O)=O Chemical compound OC([C@@H](CCC1)CN1S(C1=C(C(F)(F)F)C(Cl)=CC=C1)(=O)=O)=O QIDIKMICSNJEOW-QMMMGPOBSA-N 0.000 description 2
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 2
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000003416 augmentation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
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- 230000000699 topical effect Effects 0.000 description 2
- XJLSEXAGTJCILF-YFKPBYRVSA-N (S)-nipecotic acid Chemical compound OC(=O)[C@H]1CCCNC1 XJLSEXAGTJCILF-YFKPBYRVSA-N 0.000 description 1
- -1 (trifluoromethyl)phenyl Chemical group 0.000 description 1
- DDNCGZHXOHKKNQ-UHFFFAOYSA-N 3-chloro-2-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=C(Cl)C=CC=C1S(Cl)(=O)=O DDNCGZHXOHKKNQ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- 101150069374 Serpina1 gene Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940038528 aralast Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229940035482 glassia Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical class N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229940099982 prolastin Drugs 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229940032528 zemaira Drugs 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- oci-Antitrypsin is a member of the serpin superfamily produced by the liver and secreted into the blood. It inhibits a variety of serine proteases, especially neutrophil elastase. When blood levels of A1AT are low, excessive neutrophil elastase activity degrades lung tissue resulting in respiratory complications, such as chronic obstructive pulmonary disease (COPD).
- COPD chronic obstructive pulmonary disease
- A1AT in blood is 0.9-2.3 g/L. Levels lower than this are typical of oci-antitrypsin deficiency (A1AD or AATD), a genetic disorder caused by mutations in the SERPINA1 gene, coding for A1AT.
- the Z mutation the most common cause of AATD, is the substitution of glutamate to lysine at position 366 of A1AT (UniProtKB - P01009 (A1AT_HUMAN)), corresponding to position 342 in the mature protein (Z A1AT).
- the Z mutation affects the folding of A1AT resulting in only a small fraction acquiring the native/active state. The remainder is either cleared as misfolded protein or accumulates in the liver as stable polymers.
- homozygous carriers of the Z mutation have plasma levels of A1AT that are 10-15% of normal, predisposing carriers to COPD.
- Accumulation of Z A1AT polymers in liver cells predisposes carriers to cirrhosis, liver cancer and other liver pathologies.
- the current treatment for the lung manifestation of AATD involves augmentation therapy using A1AT concentrates prepared from the plasma of blood donors.
- the US FDA has approved the use of four A1AT products: Prolastin, Zemaira, Glassia, and Aralast. Dosing is via once weekly intravenous infusion. Augmentation therapy has been demonstrated to slow progression of COPD.
- the liver manifestations of AATD e.g. cirrhosis and cancer
- Investigational approaches to improved treatment of the liver manifestations include inhibition of Z A1AT polymerisation and increased clearance of polymers through the activation of autophagy. Investigational approaches to improved treatment of both the lung and the liver manifestations are directed towards improvement of Z A1AT folding and secretion.
- Ri , R2, R3 and R4 are each independently selected from chloride, fluoride, trifluoromethyl, -O-methyl and hydrogen,
- Also provided according to the invention is a mixture of the two enantiomers of any compound according to formula (I), wherein the mixture is either racemic or has one enantiomer in excess of the other enantiomer.
- the compound or mixture of the invention may be in a pharmaceutically acceptable salt form or crystalline form.
- pharmaceutically acceptable salt refers to a pharmaceutically acceptable mono organic or inorganic salt of the compound of the invention. This may include those derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, l-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminium hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like.
- bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, l-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminium hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like.
- bases such as sodium hydroxide, potassium hydroxide, lithium hydro
- a pharmaceutical composition comprising the compound or mixture of the invention as described herein and a pharmaceutically or therapeutically acceptable excipient or carrier.
- pharmaceutically or therapeutically acceptable excipient or carrier refers to a solid or liquid filler, diluent or encapsulating substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the host, which may be either humans or animals, to which it is administered.
- a variety of pharmaceutically acceptable carriers such as those well known in the art may be used.
- Non-limiting examples include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water.
- administration of the medicament may be via oral, subcutaneous, direct intravenous, slow intravenous infusion, continuous intravenous infusion, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracistemal, intraperitoneal, transdermal, topical, transmucosal, buccal, sublingual, transmucosal, inhalation, intranasal, intra-atricular, intranasal, rectal or ocular routes.
- the medicament may be formulated in discrete dosage units and can be prepared by any of the methods well known in the art of pharmacy.
- Administration of the medicament may for example be in the form of oral solutions and suspensions, tablets, capsules, lozenges, effervescent tablets, transmucosal films, suppositories, buccal products, oral mucoretentive products, topical creams, ointments, gels, films and patches, transdermal patches, abuse deterrent and abuse resistant formulations, sterile solutions suspensions and depots for parenteral use, and the like, administered as immediate release, sustained release, delayed release, controlled release, extended release and the like.
- Another aspect of the invention is the use of the compound or mixture of the invention as defined herein in the manufacture of a medicament for the treatment of a disease or disorder.
- a further aspect of the invention is the compound or mixture of the invention for use as an inducer of Z A1AT secretion.
- the invention also encompasses a method of treating a disease or disorder, comprising the step of administering the compound or mixture or the pharmaceutical composition of the invention as defined herein to a patient in need thereof.
- the invention further encompasses the use of a compound or mixture of the invention as an inducer of Z A1AT secretion.
- the use may be in the treatment of a disease or disorder. Additionally or alternatively, the use may be in vitro , for example in an in vitro assay.
- a disease or disorder suitable for treatment according to the relevant aspects of the invention is one which is characterised by low plasma levels of A1AT, for example AATD.
- the invention also provides the use of a racemic compound of formula (I) in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is AATD.
- racemic compound of formula (I) as an inducer of Z A1AT secretion.
- the use of a numerical range in this description is intended unambiguously to include within the scope of the invention all individual integers within the range and all the combinations of upper and lower limit numbers within the broadest scope of the given range.
- compositions comprising as active ingredient a compound
- this terminology is intended to cover both compositions in which other active ingredients may be present and also compositions which consist only of one active ingredient as defined.
- (S)- l-((3-chloro-2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared using the following synthesis procedure.
- (S)-Piperidine-3-carboxylic acid (7.7 mmol), potassium hydroxide (7.7 mmol) and potassium carbonate (15.4 mmol) were added to water (20ml) and stirred.
- 3-Chloro-2- (trifluoromethyl)benzenesulfonyl chloride (7.7 mmol) was added and the reaction was stirred at room temperature for 3 hours.
- the reaction was cooled to 0°C and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n-pentane to give (S)-l-((3-chloro-2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3- carboxylic acid.
Abstract
The invention relates to compounds of formula (I) wherein R1-R4, m and n are as described in the application, and their medical uses, for example for use in the treatment of α1-antitrypsin deficiency (A1AD or AATD).
Description
Compounds and their Use for the Treatment of cci-Antitrypsin Deficiency
The invention relates to certain carboxylic acids and their medical use. oci-Antitrypsin (A1AT) is a member of the serpin superfamily produced by the liver and secreted into the blood. It inhibits a variety of serine proteases, especially neutrophil elastase. When blood levels of A1AT are low, excessive neutrophil elastase activity degrades lung tissue resulting in respiratory complications, such as chronic obstructive pulmonary disease (COPD).
The reference range of A1AT in blood is 0.9-2.3 g/L. Levels lower than this are typical of oci-antitrypsin deficiency (A1AD or AATD), a genetic disorder caused by mutations in the SERPINA1 gene, coding for A1AT. The Z mutation, the most common cause of AATD, is the substitution of glutamate to lysine at position 366 of A1AT (UniProtKB - P01009 (A1AT_HUMAN)), corresponding to position 342 in the mature protein (Z A1AT). The Z mutation affects the folding of A1AT resulting in only a small fraction acquiring the native/active state. The remainder is either cleared as misfolded protein or accumulates in the liver as stable polymers. As a consequence of the misfolding, homozygous carriers of the Z mutation (ZZ) have plasma levels of A1AT that are 10-15% of normal, predisposing carriers to COPD. Accumulation of Z A1AT polymers in liver cells predisposes carriers to cirrhosis, liver cancer and other liver pathologies.
The current treatment for the lung manifestation of AATD involves augmentation therapy using A1AT concentrates prepared from the plasma of blood donors. The US FDA has approved the use of four A1AT products: Prolastin, Zemaira, Glassia, and Aralast. Dosing is via once weekly intravenous infusion. Augmentation therapy has been demonstrated to slow progression of COPD. The liver manifestations of AATD (e.g. cirrhosis and cancer) are treated with steroids and liver transplantation. Investigational approaches to improved treatment of the liver manifestations include inhibition of Z A1AT polymerisation and increased clearance of polymers through the activation of autophagy. Investigational
approaches to improved treatment of both the lung and the liver manifestations are directed towards improvement of Z A1AT folding and secretion.
A prior art search based on the structure of l-((2- (trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was conducted. The closest prior art molecule identified by the search was the racemic compound, l-((2- (trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid (CAS registry number 891392-68-0). This compound is listed as commercially available from Aurora, ChemDiv and the FCH Group but no publications are recorded. No pharmaceutical compositions or uses are known.
According to one aspect of the present invention, there is provided a compound of formula
(I):
wherein
• Ri , R2, R3 and R4 are each independently selected from chloride, fluoride, trifluoromethyl, -O-methyl and hydrogen,
• m and n are independently 1, 2 or 3, but the combination where both n and m are 1 is excluded,
• when the combination of m and n results in a chiral centre, optionally both enantiomers and the racemic mixture are included, and the compound is
Also provided according to the invention is a mixture of the two enantiomers of any compound according to formula (I), wherein the mixture is either racemic or has one enantiomer in excess of the other enantiomer.
The compound or mixture of the invention may be in a pharmaceutically acceptable salt form or crystalline form.
The term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable mono organic or inorganic salt of the compound of the invention. This may include those derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, l-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminium hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like. For other
examples of pharmaceutically acceptable salts, reference can be made to Gould (1986, Int J Pharm 33: 201-217).
According to a further aspect of the invention, there is a provided a pharmaceutical composition comprising the compound or mixture of the invention as described herein and a pharmaceutically or therapeutically acceptable excipient or carrier.
The term “pharmaceutically or therapeutically acceptable excipient or carrier” refers to a solid or liquid filler, diluent or encapsulating substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the host, which may be either humans or animals, to which it is administered. Depending upon the particular route of administration, a variety of pharmaceutically acceptable carriers such as those well known in the art may be used. Non-limiting examples include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water.
All suitable modes of administration are contemplated according to the invention. For example, administration of the medicament may be via oral, subcutaneous, direct intravenous, slow intravenous infusion, continuous intravenous infusion, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracistemal, intraperitoneal, transdermal, topical, transmucosal, buccal, sublingual, transmucosal, inhalation, intranasal, intra-atricular, intranasal, rectal or ocular routes. The medicament may be formulated in discrete dosage units and can be prepared by any of the methods well known in the art of pharmacy.
All suitable pharmaceutical dosage forms are contemplated. Administration of the medicament may for example be in the form of oral solutions and suspensions, tablets, capsules, lozenges, effervescent tablets, transmucosal films, suppositories, buccal products, oral mucoretentive products, topical creams, ointments, gels, films and patches, transdermal patches, abuse deterrent and abuse resistant formulations, sterile solutions suspensions and depots for parenteral use, and the like, administered as immediate
release, sustained release, delayed release, controlled release, extended release and the like.
Another aspect of the invention is the use of the compound or mixture of the invention as defined herein in the manufacture of a medicament for the treatment of a disease or disorder.
A further aspect of the invention is the compound or mixture of the invention for use as an inducer of Z A1AT secretion.
Further provided is the compound or mixture of the invention as defined herein for use in the treatment of a disease or disorder.
The invention also encompasses a method of treating a disease or disorder, comprising the step of administering the compound or mixture or the pharmaceutical composition of the invention as defined herein to a patient in need thereof.
The invention further encompasses the use of a compound or mixture of the invention as an inducer of Z A1AT secretion. The use may be in the treatment of a disease or disorder. Additionally or alternatively, the use may be in vitro , for example in an in vitro assay.
A disease or disorder suitable for treatment according to the relevant aspects of the invention is one which is characterised by low plasma levels of A1AT, for example AATD.
The invention also provides the use of a racemic compound of formula (I) in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is AATD.
Also provided is the use of a racemic compound of formula (I) as an inducer of Z A1AT secretion.
The use of a numerical range in this description is intended unambiguously to include within the scope of the invention all individual integers within the range and all the combinations of upper and lower limit numbers within the broadest scope of the given range.
As used herein, the term “comprising” is to be read as meaning both comprising and consisting of. Consequently, where the invention relates to a “pharmaceutical composition comprising as active ingredient” a compound, this terminology is intended to cover both compositions in which other active ingredients may be present and also compositions which consist only of one active ingredient as defined.
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 non-limiting examples of the present invention will now be described.
Experimental
General Method
Compounds of formula 1 were prepared using the following synthetic procedure.
Scheme 1
In Scheme 1 above, Ri , n and m have the same meanings as set out herein.
The carboxylic acid (1 equivalent), potassium hydroxide (1 equivalent) and potassium carbonate (2 equivalents) were added to water and stirred. The sulfonyl chloride (1 equivalent) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0°C and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n-pentane to give the compound of formula (I).
Synthesis of specific examples
Example 1: (R)-l-((3-chloro-2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3- carboxylic acid
(S)- l-((3-chloro-2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared using the following synthesis procedure.
(S)-Piperidine-3-carboxylic acid (7.7 mmol), potassium hydroxide (7.7 mmol) and potassium carbonate (15.4 mmol) were added to water (20ml) and stirred. 3-Chloro-2- (trifluoromethyl)benzenesulfonyl chloride (7.7 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0°C and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n-pentane to give (S)-l-((3-chloro-2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3- carboxylic acid.
Example 2: (R)- 1 -((3 -chloro-2-(trifluoromethyl)phenyl) sulfonyl)piperidine-3 - carboxylic acid
(R)-l-((3-Chloro-2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared in the same manner as (S)-l-((3-chloro-2-
(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid, but using (R)-piperidine- 3-carboxylic acid.
Example 3
The following compounds were also prepared using the general method as set out above.
Claims
Claims
1. A compound of formula (I):
wherein
• Ri , R2, R3 and R4 are independently selected from chloride, fluoride, trifluoromethyl, -O-methyl and hydrogen,
• m and n are independently 1, 2 or 3, but the combination where both n and m are 1 is excluded,
• when the combination of m and n results in a chiral centre, optionally both enantiomers and the racemic mixture are included, and the compound is
2. A mixture of the two enantiomers of any compound according to claim 1, wherein the mixture is either racemic or has one enantiomer in excess of the other enantiomer.
3. The compound or mixture according to any preceding claim in a pharmaceutically acceptable salt form.
4. A pharmaceutical composition comprising a compound or mixture according to any one of claims 1 to 3 and a pharmaceutically or therapeutically acceptable excipient or carrier.
5. Use of a compound or mixture according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a disease or disorder.
6. A compound or mixture according to any one of claims 1 to 3 for use in the treatment of a disease or disorder.
7. A compound or mixture according to any one of claims 1 to 3 for use as an inducer of Z A1AT secretion.
8. A method of treating a disease or disorder, comprising the step of administering a compound or mixture according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, to a patient in need thereof.
9. Use of a compound or mixture according to any one of claims 1 to 3 in the treatment of a disease or disorder.
10. The use according to claim 9 as an inducer of Z A1AT secretion.
11. The use according to either of claim 9 or claim 10 wherein the use is in vitro.
12. The use according to claim 5, the compound or mixture for use according to claim 6, the method of treatment according to claim 8, or the use according to any one of claims 9 to 11, wherein the disease or disorder is AATD.
15. Use of a racemic compound of formula (I) as defined in any of claims 1 to 3 in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is AATD.
16. Use of a racemic compound of formula (I) as defined in any of claims 1 to 3 as an inducer of Z A1AT secretion.
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|---|---|---|---|
| GBGB2108542.8A GB202108542D0 (en) | 2021-06-15 | 2021-06-15 | Compounds and their use for the treatment of alpha1-antitrypsin deficiency |
| GB2108542.8 | 2021-06-15 |
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| WO2022263817A1 true WO2022263817A1 (en) | 2022-12-22 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113542A2 (en) * | 2004-05-20 | 2005-12-01 | Elan Pharmaceuticals, Inc. | N-cyclic sulfonamido inhibitors of gamma secretase |
| EP2471363A1 (en) * | 2010-12-30 | 2012-07-04 | Bayer CropScience AG | Use of aryl-, heteroaryl- and benzylsulfonamide carboxylic acids, -carboxylic acid esters, -carboxylic acid amides and -carbonitriles and/or its salts for increasing stress tolerance in plants |
| WO2020120992A1 (en) * | 2018-12-14 | 2020-06-18 | Z Factor Limited | COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY |
| WO2021067584A1 (en) * | 2019-10-02 | 2021-04-08 | Vertex Pharmaceuticals Incorporated | Methods of treatment for alpha-1 antitrypsin deficiency |
| WO2021116703A1 (en) * | 2019-12-13 | 2021-06-17 | Z Factor Limited | COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY |
-
2021
- 2021-06-15 GB GBGB2108542.8A patent/GB202108542D0/en not_active Ceased
-
2022
- 2022-06-15 WO PCT/GB2022/051503 patent/WO2022263817A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113542A2 (en) * | 2004-05-20 | 2005-12-01 | Elan Pharmaceuticals, Inc. | N-cyclic sulfonamido inhibitors of gamma secretase |
| EP2471363A1 (en) * | 2010-12-30 | 2012-07-04 | Bayer CropScience AG | Use of aryl-, heteroaryl- and benzylsulfonamide carboxylic acids, -carboxylic acid esters, -carboxylic acid amides and -carbonitriles and/or its salts for increasing stress tolerance in plants |
| WO2020120992A1 (en) * | 2018-12-14 | 2020-06-18 | Z Factor Limited | COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY |
| WO2021067584A1 (en) * | 2019-10-02 | 2021-04-08 | Vertex Pharmaceuticals Incorporated | Methods of treatment for alpha-1 antitrypsin deficiency |
| WO2021116703A1 (en) * | 2019-12-13 | 2021-06-17 | Z Factor Limited | COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY |
Non-Patent Citations (4)
| Title |
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| DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 21 November 2016 (2016-11-21), XP002807232, Database accession no. 2035392-14-2 * |
| DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 24 November 2016 (2016-11-24), XP002807231, Database accession no. 2036545-67-0 * |
| DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 28 November 2016 (2016-11-28), XP002807230, Database accession no. 2039706-22-2 * |
| GOULD, INT J PHARM, vol. 33, 1986, pages 201 - 217 |
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