# US 8,785,659 B2 · Method for the production of sulphonylpyrroles as HDAC inhibitors

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- Number: US 8,785,659 B2
- Document ID: US8785659B2
- Status: Granted
- Kind: B2
- Application number: 12/921,928
- Filed: 2009-03-11
- Published: 2011-05-05
- Granted: 2014-07-22
- Earliest claimed: 2008-03-12
- Assignees: 4Sc AG
- Applicants: Matthias Müller; Bernd Müller; Thomas Maier
- Inventors: Matthias Müller; Bernd Müller; Thomas Maier
- Web page: https://patentgrep.com/patent/US8785659B2

## CPC

- C07D 207/48: Sulfur atoms
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Process for the preparation of a compound of formula (I) wherein R1, R2, R3, R4, R5 and R6 have the meanings as defined in the specification, comprising the step of reacting an acrylic acid chloride compound of formula (II′): wherein R1, R2, R3, R4, R5 and R6 have the meanings as defined in the specification, with aqueous hydroxylamine and optionally converting the resulting compound into an acid addition salt thereof.

## Claims

### Claim 1

A process for preparing a compound of formula I:
wherein
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1,
T1 is a bond,
Q1 is Ar1, Aa1, Hh1, or Ah1,
Ar1 is phenyl, or R61- and/or R62-substituted phenyl,
R61 is 1-4C-alkyl, or -T2-N(R611)R612,
either
T2 is a bond, and
R611 is 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, or phenyl-1-4C-alkyl,
R612 1-4C-alkyl, or 1-4C-alkoxy-2-4C-alkyl, or
R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1,
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, or pyrrolidino,
or
T2 is 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen, and
R611 is 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, or phenyl-1-4C-alkyl,
R612 is 1-4C-alkyl, or 1-4C-alkoxy-2-4C-alkyl, or
R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1,
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino, imidazole, pyrrolo or pyrazolo,
R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylamino, or 1-4C-alkylsulphonylamino,
Aa1 is a bisaryl radical made up of two aryl groups, which are independently selected from the group consisting of phenyl and naphthyl, and which are linked together via a single bond,
Hh1 is a bisheteroaryl radical made up of two heteroaryl groups, which are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and which are linked together via a single bond,
Ah1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from the group consisting of phenyl and naphthyl, wherein said heteroaryl and aryl groups are linked together via a single bond, wherein Aa1, Hh1 and Ah1 may be optionally substituted by R63 and/or R64,
R63 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkoxy, trifluoromethyl, cyano, halogen, completely or predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylsulphonylamino, tolylsulphonylamino, phenylsulphonylamino, 1-4C-alkylcarbonylamino, carbamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulphonyl, or -T3-N(R631)R632,
T3 is a bond, 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen,
R631 is 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, or phenyl-1-4C-alkyl,
R632 1-4C-alkyl, or 1-4C-alkoxy-2-4C-alkyl, or
R631 and R632 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het2,
Het2 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino, imidazole, pyrrolo or pyrazolo, and
R64 is 1-4C-alkyl, 1-4C-alkoxy or halogen,
comprising reacting an acrylic acid chloride compound of formula II′:
wherein R1, R2, R3, R4, R5 and R6 have the meanings as defined for the compound of formula I,
with aqueous hydroxylamine, and
optionally converting the resulting compound into an acid addition salt thereof.

### Claim 2 (depends on 1)

A process according to claim 1, further comprising
i) providing a compound of formula II:
wherein R1, R2, R3, R4, R5 and R6 and have the meanings as defined for the compound of formula I,
and
ii) converting the compound of formula II into its acid chloride of formula II′.

### Claim 3 (depends on 2)

A process according to claim 2, wherein ii) is carried out with thionyl chloride or oxalyl chloride.

### Claim 4 (depends on 2)

A process according to claim 2, wherein i) is carried out by synthesizing the compound of formula II by converting a compound of formula V:
wherein R1, R2, R4 and R5 have the meanings as defined for the compound of formula II, to a compound of formula IV:
wherein R1, R2, R3, R4 and R5 have the meanings as defined for the compound of formula II and PG1 stands for a temporary protective group for the carboxyl group, and
reacting the compound of formula IV with a compound of formula R6-SO2—X, wherein R6 is as defined for the compound of formula II and X is a leaving group, to give a compound of formula III:
wherein R1, R2, R3, R4 and R6 have the meanings as defined for the compound of formula II and PG1 stands for a temporary protective group for the carboxyl group, and
removing the protective group PG1 to obtain a compound of formula II.

### Claim 5 (depends on 1)

A process according to claim 1 wherein the compound of formula I is obtained in the form of the free base.

### Claim 6 (depends on 1)

A process according to claim 1 wherein the compound of formula I is directly obtained in the form of its hydrochloride salt by reaction of a compound of formula II′ with aqueous hydroxylamine.

### Claim 7 (depends on 1)

A process according to claim 1 for the preparation of a salt of a compound of formula I other than the hydrochloride, comprising reacting the free base of a compound of formula I with an acid or acid derivative to form the corresponding acid addition salt, or converting the acid addition salt of a compound of formula I into another acid addition salt.

### Claim 8 (depends on 7)

A process according to claim 7, wherein the acid addition salt of the compounds of formula I other than the hydrochloride is the methanesulfonate.

### Claim 9 (depends on 1)

A process for preparing a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, comprising synthesizing the compound of formula I or its acid addition salt according to claim 1 and formulating the resulting compound with a pharmaceutically acceptable excipient.