WO2022263820A1 - COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY - Google Patents

COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY Download PDF

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WO2022263820A1
WO2022263820A1 PCT/GB2022/051506 GB2022051506W WO2022263820A1 WO 2022263820 A1 WO2022263820 A1 WO 2022263820A1 GB 2022051506 W GB2022051506 W GB 2022051506W WO 2022263820 A1 WO2022263820 A1 WO 2022263820A1
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compound
phenyl
disorder
disease
trifluoromethyl
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PCT/GB2022/051506
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Nigel Ramsden
David John Fox
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Z Factor Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

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 is optionally substituted phenyl
  • X is O, NH or NR 2 ;
  • the phenyl may be optionally substituted with one or more halo(Ci-Cs)alkyl groups, for example one or more tri-halo(Ci-C5)alkyl groups.
  • the phenyl may be substituted with one or more trifluoromethyl groups.
  • the phenyl may be substituted with a trifluoromethyl group at the 2 position.
  • Ri may be phenyl substituted with a trifluoromethyl group at the 2 position, wherein the phenyl is optionally further substituted at the 3, 4, 5 or 6 positions.
  • the compound of formula (I) may not be
  • the compound of formula (I) may be a compound of formula (IV) wherein X and R2 are as defined above.
  • the compound of formula (I) may be any organic compound having the same or chirality.
  • the compound of formula (I) may be any organic compound having the same or chirality.
  • the compound of formula (I) may be Herein, the substituent positions on the benzene ring are numbered according to the following formula:
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to compounds of formula (I): wherein R1 and X are as defined 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):
Figure imgf000003_0001
wherein
Ri is optionally substituted phenyl;
X is O, NH or NR2;
R2 is methyl or -C=OCH3.
The phenyl may be optionally substituted with one or more halo(Ci-Cs)alkyl groups, for example one or more tri-halo(Ci-C5)alkyl groups.
The phenyl may be substituted with one or more trifluoromethyl groups. The phenyl may be substituted with a trifluoromethyl group at the 2 position.
Ri may be phenyl substituted with a trifluoromethyl group at the 2 position, wherein the phenyl is optionally further substituted at the 3, 4, 5 or 6 positions. The compound of formula (I) may not be
Figure imgf000004_0001
The compound of formula (I) may be a compound of formula (IV)
Figure imgf000004_0002
wherein X and R2 are as defined above.
The compound of formula (I) may be
Figure imgf000004_0003
The compound of formula (I) may be
Figure imgf000004_0004
Herein, the substituent positions on the benzene ring are numbered according to the following formula:
Figure imgf000005_0001
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).
Experimental
Example 1: (S)-4-((2-(Trifluoromethyl)phenyl)sulfonyl)morpholine-2-carboxylic add
(S)-4-((2-(Trifluoromethyl)phenyl)sulfonyl)morpholine-2-carboxylic acid was prepared using the following synthesis procedure.
Figure imgf000009_0001
(2S)-Morpholine-2-carboxylic acid (7.7 mmol), potassium hydroxide (7.7 mmol) and potassium carbonate (15.4 mmol) were added to water (20ml) and stirred. 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)-4-((2-(trifluoromethyl)phenyl)sulfonyl)morpholine-2- carboxylic acid.
Example 2: (R)-4-((2-(Trifluoromethyl)phenyl)sulfonyl)morpholine-2-carboxylic add
(R)-4-((2-(trifluoromethyl)phenyl)sulfonyl)morpholine-2-carboxylic acid was prepared in the same manner as (S)-4-((2-(trifluoromethyl)phenyl)sulfonyl)morpholine-2- carboxylic acid, but using (2R)-morpholine-2-carboxylic acid.
Example 3: (S)-4-((2-(Trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic add
(S)-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid was prepared using the following synthesis procedure.
Figure imgf000010_0001
(2S)-l-/er/-Butoxycarbonyl-piperazine-2-carboxylic acid (synthesised by an analogous method to that for the (R)-enantiomer in US 20030134846 Al) (7.7 mmol), potassium hydroxide (7.7 mmol) and potassium carbo nate (15.4 mmol) were added to water (20ml) and stirred. 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-/er/-butoxycarbonyl-4-((2- (trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid. This acid was dissolved in trifluoroacetic acid (10ml) and the reaction was stirred at 50 °C for 4 hours. The trifluoroacetic acid was removed in vacuo. The residue was dissolved in water and added to Dowex 50X W8 resin (acid form), and then eluted with dilute aqueous ammonia, and reduced in vacuo to give (S)-4-((2- (trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid.
Example 4: (R)-4-((2-(Trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid
(R)-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid was prepared in the same manner as (S)-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2- carboxylic acid, but using (2R)-l-/er/-butoxycarbonyl-piperazine-2-carboxylic acid (synthesised according to US 20030134846 Al). Example 5: (S)-l-Methyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2- carboxylic acid
(S)- l-Methyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid was prepared using the following synthesis procedure.
Figure imgf000011_0001
A mixture of (S)-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid (5 mmol), 37% formaldehyde (10 mmol), and formic acid (20 mmol) in MeOH (10 mL) was refluxed for 20 h. Reaction was reduced in vacuo and the residue was dissolved in water and added to Dowex 50X W8 resin (acid form), and then eluted with dilute aqueous ammonia, and reduced in vacuo to give (S)-l-methyl-4-((2- (trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid.
Example 6: (R)-l-Methyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2- carboxylic acid
(R)-l-Methyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid was prepared in the same manner as (S)-l-methyl-4-((2-
(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid, but using (R)-4-((2- (trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid.
Example 7: (S)-l-Acetyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2- carboxylic acid
(S)- l-Acetyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid was prepared using the following synthesis procedure.
Figure imgf000012_0001
(S)-4-((2-(Trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid (7.7 mmol), and potassium carbonate (15.4 mmol) were added to water (20ml) and stirred. Acetic anhydride (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- acetyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid.
Example 8: (R) - 1 - Acetyl-4- ((2- (trifluoromethyl)phenyl)sulfonyl)piperazine-2- carboxylic acid
(R)-l-Acetyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid was prepared in the same manner as (S)-l-acetyl-4-((2-
(trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid, but using (R)-4-((2- (trifluoromethyl)phenyl)sulfonyl)piperazine-2-carboxylic acid.

Claims

Claims
1. A compound of formula (I):
Figure imgf000013_0001
wherein
Ri is optionally substituted phenyl;
X is O, NH or NR2;
R2 is methyl or -C=OCH3.
2. The compound of claim 1, wherein the phenyl is substituted with one or more halo(Ci- C5)alkyl groups, for example one or more tri-halo(Ci-C5)alkyl groups.
3. The compound of claim 1 or 2, wherein the phenyl is substituted with one or more trifluoromethyl groups.
4. The compound of any preceding claim, wherein Ri is phenyl substituted with a trifluoromethyl group at the 2 position, and wherein the phenyl is optionally further substituted at the 3, 4, 5 or 6 positions.
5. The compound of any preceding claim, wherein the compound of formula (I) is not
Figure imgf000013_0002
6. The compound of any preceding claim, wherein the compound of formula (I) is a compound of formula (IV)
Figure imgf000014_0001
wherein X is O, NH or NR2; and R2 is methyl or -C=OCH3.
7. The compound of any preceding claim, wherein the compound is
Figure imgf000014_0002
8. A mixture of the two enantiomers of any compound according to any preceding claim, wherein the mixture is either racemic or has one enantiomer in excess of the other enantiomer.
9. The compound or mixture according to any preceding claim in a pharmaceutically acceptable salt form.
10. A pharmaceutical composition comprising a compound or mixture according to any preceding claim and a pharmaceutically or therapeutically acceptable excipient or carrier.
11. Use of a compound or mixture according to any preceding claim in the manufacture of a medicament for the treatment of a disease or disorder.
12. A compound or mixture according to any one of claims 1 to 9 for use in the treatment of a disease or disorder.
13. A compound or mixture according to any one of claims 1 to 9 for use as an inducer ofZ AlAT secretion.
14. 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 9, or a pharmaceutical composition according to claim 10, to a patient in need thereof.
15. Use of a compound or mixture according to any one of claims 1 to 9 in the treatment of a disease or disorder.
16. The use according to claim 15 as an inducer of Z A1AT secretion.
17. The use according to either of claim 15 or claim 16 wherein the use is in vitro.
18. The use according to claim 11, the compound or mixture for use according to claim 12, the method of treatment according to claim 14, or the use according to any one of claims 15 to 17, wherein the disease or disorder is AATD.
19. Use of a racemic compound of formula (I) as defined in any of claims 1 to 7 in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is AATD.
20. Use of a racemic compound of formula (I) as defined in any of claims 1 to 7 as an inducer of Z A1AT secretion.
PCT/GB2022/051506 2021-06-15 2022-06-15 COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY WO2022263820A1 (en)

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