# US 8,772,508 B2 · Inhibitors of glutaminyl cyclase

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- Number: US 8,772,508 B2
- Document ID: US8772508B2
- Status: Granted
- Kind: B2
- Application number: 12/105,730
- Filed: 2008-04-18
- Published: 2008-11-27
- Granted: 2014-07-08
- Earliest claimed: 2007-04-18
- Assignees: Probiodrug AG
- Applicants: Mirko Buchholz; Ulrich Heiser; Antje Hamann
- Inventors: Mirko Buchholz; Ulrich Heiser; Antje Hamann
- Web page: https://patentgrep.com/patent/US8772508B2

## CPC

- C07D 233/61: with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- 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 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 405/12: 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

Compounds of formula (I), combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers, stereoisomers and polymorphs thereof, wherein A, B and R1 are as defined throughout the description and the claims.

## Claims

### Claim 1

A compound of formula (I),
or a pharmaceutically acceptable salt, including all tautomers and stereoisomers thereof wherein:
R1 represents alkenyl, wherein the double bond is not adjacent to the nitrogen; carbocyclyl; —C1-6alkyl-carbocyclyl; heterocyclyl; —C1-6alkyl-heterocyclyl; aryl; heteroaryl; —C1-6alkylaryl; —C1-6alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused to heterocyclyl;
in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and
in which any of the aforesaid phenyl, aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SO2C1-4-alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl,
—SO2C3-8cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6-alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4-alkyl,
—C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl), —C(O)OC1-6alkyl, —SOC1-4alkyl and —SOC3-6cycloalkyl; or
R1 represents phenyl substituted by phenyl, or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; or
R1 represents phenyl substituted by benzyloxy- in which any of the aforesaid phenyl or benzyloxy groups may optionally be substituted on the ring by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; and
A represents
wherein Y represents a C2-5 alkylene chain, which may optionally be substituted by one or two methyl groups or may optionally be substituted by two alkylene substituents at the same position wherein the two alkylene substituents are joined to each other to form a C3-5-spiro-cycloalkyl group and
R2, R3 and R4 independently represent H or C1-2alkyl, provided that R2 and R3 and R4 do not all represent H; or
A represents
wherein Z represents a bond, —CH2—, —CH2—CH2—, —CH(Me)- , —CH(Me)-CH2— or —CH2—CH(Me)- and
R5 and R6 independently represent H or C1-2alkyl and
B represents H or methyl.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein
R1 represents alkenyl, wherein the double bond is not adjacent to the nitrogen; carbocyclyl; —C1-6alkyl-carbocyclyl; heterocyclyl; —C1-6alkyl-heterocyclyl; aryl; heteroaryl; —C1-6alkylaryl; —C1-6alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused to heterocyclyl;
in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and
in which any of the aforesaid phenyl, aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —C1-6thioalkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2 and —C(O)NH(C1-4alkyl); or
R1 represents phenyl substituted by phenyl, or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R1 represents optionally substituted aryl.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R1 is aryl, optionally substituted by one or more substituents selected from C1-6alkyl, C1-6alkoxy-, C1-6haloalkyl and halogen.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R1 represents optionally substituted carbocyclyl.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein R1 represents optionally substituted phenyl fused to optionally substituted heterocyclyl.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein A represents
wherein R2, R3, R4 and Y are as defined in claim 1.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein
R2 represents H,
R3 represents H and
R4 represents methyl.

### Claim 9 (depends on 7)

A compound according to claim 7 wherein Y represents an unsubstituted C2-5 alkylene chain.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein Y represents —(CH2)3— or —(CH2)4—.

### Claim 11 (depends on 7)

A compound according to claim 7 wherein A represents

### Claim 12 (depends on 1)

A compound according to claim 1 wherein A represents
wherein R5, R6 and Z are as defined in claim 1.

### Claim 13 (depends on 12)

A compound according to claim 12 wherein
R5 represents H and
R6 represents H.

### Claim 14 (depends on 12)

A compound according to claim 12 wherein Z represents a bond, —CH2— or —CH2—CH2—.

### Claim 15 (depends on 1)

A compound according to claim 1 wherein B represents H.

### Claim 16 (depends on 1)

A compound according to claim 1 as defined in any one of examples 1 to 18 selected from:
(1) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)cyclohexanamine,
(2) N-(1-(3-(5-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-2,4-dimethoxybenzenamine,
(3) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-3,4,5-trimethoxybenzenamine,
(4) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-3,4-dimethoxybenzenamine,
(5) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine,
(6) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-(trifluoromethyl)benzenamine,
(7) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-chlorobenzenamine,
(8) N-(1-(4-(5-methyl-1H-imidazol-1-yl)butylamino)-2-nitrovinyl)cyclohexanamine,
(9) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)benzo[d][1,3]dioxol-5-amine,
(10) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)naphthalen-1-amine,
(8) N-(1-(4-(5-methyl-1H-imidazol-1-yl)butylamino)-2-nitrovinyl)cyclohexanamine
(9) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)benzo[d][1,3]dioxol-5-amine
(10) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)naphthalen-1-amine
(11) N-(1-(3-(4-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-chlorobenzenamine
(12) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-4-(trifluoromethyl)benzenamine
(13) N-(1-(3-(4-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine
(14) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-3,4-dimethoxybenzen-amine
(15) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-3,4,5-tri-methoxybenzen-amine
(16) N-(1-(3-(4-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,4-dimethoxybenzen-amine
(17) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)benzo[d]-[1,3]dioxol-5-amine and
(18) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-naphthalen-1-amine
or a pharmaceutically acceptable salt of any one thereof.

### Claim 17 (depends on 1)

A compound according to claim 1 as defined in example 8:
N-(1-(4-(5-methyl-1H-imidazol-1-yl)butylamino)-2-nitrovinyl)cyclohexanamine, or
a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 optionally in combination with one or more therapeutically acceptable diluents or carriers.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18, which comprises additionally at least one compound, selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

### Claim 20 (depends on 18)

The pharmaceutical composition of claim 18, which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.

### Claim 21 (depends on 1)

A process for preparation of a compound of formula (I) according to claim 1, which comprises reaction of a compound of formula (II)
wherein R7 represents C1-6alkyl and R1 is as defined in claim 1, with a compound of formula (III)
wherein A and B are as defined in claim 1.