US2022110920A1PendingUtilityA1
Compositions and methods for the treatment and prevention of neurological disorders
Est. expiryJun 21, 2038(~11.9 yrs left)· nominal 20-yr term from priority
Inventors:Rebecca AronBhaumik PandyaDaniel TardiffJeff S. PiotrowskiMatthew C. LucasBertrand Le BourdonnecKenneth RhodesRobert Scannevin
A61K 31/4196C12N 15/1137C07K 16/40A61K 31/704A61P 25/28A61K 31/7105A61K 31/4164A61K 2039/505A61K 31/4178A61K 31/496A61P 25/00A61K 31/575A61K 31/506A61K 31/4406
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Claims
Abstract
The invention provides compositions and methods for treating neurological disorders, such as amyotrophic lateral sclerosis, frontotemporal degeneration, and Alzheimer's disease, among others. Using the compositions and methods described herein, a patient having a neurological disorder, such as a neurological disorder associated with TAR-DNA binding protein (TDP)-43 aggregation, may be administered an inhibitor of cytochrome P450 (CYP450) isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alpha demethylase, so as to treat an underlying etiology of the disorder and/or to alleviate one or more symptoms of the disease. The inhibitor of CYP51A1 may be a small molecule, anti-CYP51A1 antibody or antigen-binding fragment thereof, or a compound, such as an interfering RNA molecule, that attenuates CYP51A1 expression. Patients that may be treated using the compositions and methods described herein include those that express a mutant TDP-43 isoform containing a mutation associated with TDP-43-promoted aggregation and toxicity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method a method of treating a neurological disorder in a human patient, the method comprising administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor.
2 . A method of treating a neurological disorder in a human patient identified as likely to benefit from treatment with a CYP51A1 inhibitor, the method comprising:
(i) determining that the patient is susceptible to developing TAR-DNA binding protein (TDP)-43 aggregation; and (ii) administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor.
3 . A method of treating a neurological disorder in a human patient identified as likely to benefit from treatment with a CYP51A1 inhibitor, wherein the patient has previously been determined to be susceptible to developing TDP-43 aggregation, the method comprising administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor.
4 . A method of treating a neurological disorder in a human patient identified as likely to benefit from treatment with a CYP51A1 inhibitor, the method comprising:
(i) determining that the patient expresses a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation; and (ii) administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor.
5 . A method of treating a neurological disorder in a human patient identified as likely to benefit from treatment with a CYP51A1 inhibitor, wherein the patient has previously been determined to express a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation, the method comprising administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor.
6 . A method of determining whether a human patient having a neurological disorder is likely to benefit from treatment with a CYP51A1 inhibitor, the method comprising:
(i) determining that the patient is susceptible to developing TDP-43 aggregation; (ii) identifying the patient as likely to benefit from treatment with a CYP51A1 inhibitor; and (iii) informing the patient that they have been identified as likely to benefit from treatment with a CYP51A1 inhibitor.
7 . A method of determining whether a human patient having a neurological disorder is likely to benefit from treatment with a CYP51A1 inhibitor, the method comprising:
(i) determining that the patient expresses a mutant of TDP-43 having a mutation associated with TDP-43 aggregation; (ii) identifying the patient as likely to benefit from treatment with a CYP51A1 inhibitor; and (iii) informing the patient that they have been identified as likely to benefit from treatment with a CYP51A1 inhibitor.
8 . The method of any one of claims 4 , 5 , and 7 , wherein the mutation is selected from the group consisting of Q331K, M337V, Q343R, N345K, R361S, and N390D.
9 . The method of any one of claims 1 - 8 , wherein the neurological disorder is a neuromuscular disorder.
10 . The method of claim 9 , wherein the neuromuscular disorder is selected from the group consisting of amyotrophic lateral sclerosis, congenital myasthenic syndrome, congenital myopathy, cramp fasciculation syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayre syndrome, Lambert-Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy, Stiff person syndrome, Troyer syndrome, and Guillain-Barré syndrome.
11 . The method of claim 10 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis.
12 . The method of any one of claims 1 - 8 , wherein the neurological disorder is selected from the group consisting of frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington's disease, inclusion body myopathy with early-onset Paget disease and frontotemporal dementia, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy.
13 . The method of any one of claims 1 - 12 , wherein the CYP51A1 inhibitor is a small molecule that binds to and/or inhibits the enzymatic activity of CYP51A1.
14 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (I)
wherein n is 1 or 2;
X is hydrogen, lower alkyl, lower alkoxy-lower alkyl, or a group X a of the formula:
Z is a group of the formula:
Y is a group of the formula:
R O is lower alkyl, COR 4 or C(R 5 )═CHCOR 4 ;
R is R o or is OR″;
R″ is hydrogen, lower-alkyl, lower alkanoyl, (CH 2 ) 1-6 —OH, (CH 2 ) 1-6 —O(CH 2 ) 1-6 —R 6 , or (CH 2 ) 1-6 —COR 4 ;
R 1 and R a are hydrogen, lower alkanoyl, benzoyl or (CH 2 ) 1-6 —OH;
R 2 and R b are hydrogen, Cl, Br or CF 3 ;
R 3 and R 5 are hydrogen or CH 3 ;
R 4 is hydroxy, lower-alkoxy or N(R 7 , R 8 );
R 6 is hydrogen, R g , OH or COR 4 ;
R 7 and R 8 are hydrogen or lower alkyl;
R c and R e are hydrogen, Cl, F, Br or CF 3 ;
R d is hydrogen or NH 2 ;
R f is hydrogen, CH 3 CONH—, NH 2 COCH 2 — or R 9 CH 2 CH 2 OCH 2 CH 2 O—;
R g and R 9 are phenyl or phenyl substituted by Cl, F or Br;
or a pharmaceutically acceptable salt, ester, or ether thereof.
15 . The method of claim 14 , wherein n is 1, R 1 is hydrogen, R 2 is chlorine in the 6-position of a 2-pyridyl residue, and Y is phenyl substituted in the p-position by R.
16 . The method of claim 14 , wherein X is X a , R a is hydrogen, Z is 6-chloro-2-pyridyl, and Y is phenyl substituted in the p-position by 2-ethoxyethoxy, 2-phenethoxyethoxy or methoxycarbonylmethoxy.
17 . The method of claim 14 , wherein the compound is methyl α,α′-[[[(R)-p-(2-ethoxyethoxy)-α-methylphen-ethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol]; (RS)-6-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methyl-phenethyl]amino]methyl]-2-pyridinemethanol; α,α′-[[[p-(2-ethoxyethoxy)phenethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol]; (R)-6-bromo-α-[[[(RS)-2-(6-bromo-2-pyridyl)-2-hydroxyethyl][(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]-amino]methyl]-2-pyridimidinemethanol; (R)-6-chloro-α[[[(S)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl][(R)-.alpha.-methyl-p-(2-phenethoxyethoxy)phenethyl]amino]methyl]-2-pyridinemethanol.
18 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (II)
wherein n is 1, 2, 3 or 4 and m is 0, 1, 2, 3, 4, or 5;
R 1 is a hydrogen atom, hydroxyl group, or lower C 1-6 alkoxy group;
R 2 is a hydrogen atom or an optionally substituted straight or branched lower C 1-6 alkyl group;
each X is independently fluorine, chlorine, bromine, hydroxyl group, trifluoromethyl group, 3,4-di-Cl, 2,4-di-Cl or lower C 1-6 alkoxy group, and wherein the phenyl ring containing each X is optionally fused;
or a pharmaceutically acceptable salt, ester, or ether thereof.
19 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (1), (2), (3), (13), (14), (15), or (16):
20 . The method of claim 18 , wherein n is 2, R 1 is a hydroxyl group, R 2 a methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group and X is a hydrogen atom or phenyl disubstituted with two chlorine atoms in the positions 3 and 4 or in the positions 2 and 4.
21 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (III)
wherein the dotted line ( ) is an optional bond;
X is O or S;
A is —C(H)═, —C((C 1 -C 4 )alkyl)=, —C(halo)= or —N═, when the dotted line (---) is a bond, or A is methylene or —CH((C 1 -C 4 )alkyl)-, when the dotted line (---) is not a bond;
R 1 , R 10 or R 11 are each independently H, halo, cyano, 4-, 6-, or 7-nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl;
R 2 is H;
R 3 is H or (C 1 -C 6 )alkyl;
R 4 is H, methyl, ethyl, n-propyl, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, phenyl(C 1 -C 4 )alkyl, phenylhydroxy(C 1 -C 4 )alkyl, (phenyl)((C 1 -C 4 )-alkoxy)(C 1 -C 4 )alkyl, thien-2- or -3-yl(C 1 -C 4 )alkyl or fur-2- or 3-yl(C 1 -C 4 )alkyl wherein the R 4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or
R 4 is pyrid-2-, -3- or -4-yl(C 1 -C 4 )alkyl, thiazol-2-, -4- or -5-yl(C 1 -C 4 )alkyl, imidazol-2-, -4- or -5-yl(C 1 -C 4 )alkyl, pyrrol-2- or -3-yl(C 1 -C 4 )alkyl, oxazol-2-, -4- or -5-yl(C 1 -C 4 )alkyl, pyrazol-3-, -4- or -5-yl(C 1 -C 4 )alkyl, isoxazol-3-, -4- or -5-yl(C 1 -C 4 )alkyl, isothiazol-3-, -4- or -5-yl(C 1 -C 4 )alkyl, pyridazin-3- or -4-yl(C 1 -C 4 )alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C 1 -C 4 )alkyl, pyrazin-2- or -3-yl(C 1 -C 4 )alkyl, 1,3,5-triazin-2-yl(C 1 -C 4 )alkyl; or indol-2-(C 1 -C 4 )alkyl, wherein the preceding R 4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, amino, hydroxy or cyano and the substituents are bonded to carbon; or
R 4 is R 15 -carbonyloxymethyl, wherein the R 15 is phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein the preceding R 15 rings are optionally mono- or di-substituted independently with halo, amino, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or trifluoromethyl and the mono- or di-substituents are bonded to carbon;
R 5 is H, methyl, ethyl, n-propyl, hydroxymethyl or hydroxyethyl;
R 6 is carboxy, (C 1 -C 8 )alkoxycarbonyl, benzyloxycarbonyl, C(O)NR 8 R 9 or C(O)R 12 wherein
R 8 is H, (C 1 -C 6 )alkyl, cyclo(C 3 -C 6 )alkyl, cyclo(C 3 -C 6 )alkyl(C 1 -C 5 )alkyl, hydroxy or (C 1 -C 8 )alkoxy; and
R 9 is H, cyclo(C 3 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl(C 1 -C 5 )alkyl, cyclo(C 4 -C 7 )alkenyl, cyclo(C 3 -C 7 )alkyl(C 1 -C 5 )alkoxy, cyclo(C 3 -C 7 )alkyloxy, hydroxy, methylene-perfluorinated(C 1 -C 8 )alkyl, phenyl, or a heterocycle wherein the heterocycle is pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein the heterocycle rings are carbon-nitrogen linked; or
R 9 is (C 1 -C 6 )alkyl or (C 1 -C 8 )alkoxy wherein the (C 1 -C 6 )alkyl or (C 1 -C 8 )alkoxy is optionally monosubstituted with cyclo(C 4 -C 7 )alken-1-yl, phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl or indolyl and wherein the (C 1 -C 6 )alkyl or (C 1 -C 8 )alkoxy are optionally additionally independently mono- or di-substituted with halo, hydroxy, (C 1 -C 5 )alkoxy, amino, mono-N— or di-N,N—(C 1 -C 5 )alkylamino, cyano, carboxy, or (C 1 -C 4 )alkoxycarbonyl; and
wherein the R 9 rings are optionally mono- or di-substituted independently on carbon with halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy, hydroxy(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl, mono-N— or di-N,N—(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 C 4 )alkyl, amino, mono-N— or di-N,N—(C 1 -C 4 )alkylamino, cyano, carboxy, (C 1 -C 5 )alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl and the R 9 rings may optionally be additionally mono- or di-substituted independently with (C 1 -C 5 )alkyl or halo;
optionally with the proviso that no quaternized nitrogen on any R 9 heterocycle is included;
R 12 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4dihydroisoquinolin-2-yl, 1,3-dihydrolsoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl, 2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo[c][1,2]oxazin-1-yl, 1,4-dihydro-benzo[d][1,2]oxazin-3-yl, 3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl, 3H-benzo[c]isoxazol-1-yl or azepan-1-yl,
wherein the R 12 rings are optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, hydroxy, amino, mono-N— or di-N,N—(C 1 -C 5 )alkylamino, formyl, carboxy, carbamoyl, mono-N— or di-N,N—(C 1 -C 5 )alkylcarbamoyl, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkoxy, (C 1 -C 5 )alkoxycarbonyl, benzyloxycarbonyl, (C 1 -C 5 )alkoxycarbonyl(C 1 C 5 )alkyl, (C 1 C 4 )alkoxycarbonylamino, carboxy(C 1 -C 5 )alkyl, carbamoyl(C 1 -C 5 )alkyl, mono-N— or di-N,N—(C 1 -C 5 )alkylcarbamoyl(C 1 -C 5 )alkyl, hydroxy(C 1 -C 5 )alkyl, (C 1 -C 4 )alkoxy(C 1-4 )alkyl, amino(C 1 C 4 )alkyl, mono-N— or di-N,N—(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, oxo, hydroxylmino or (C 1 -C 6 )alkoxylmino and wherein no more than two substituents are selected from oxo, hydroxylmino or (C 1 -C 6 )alkoxylmino and oxo, hydroxylmino or (C 1 -C 6 )alkoxyimino are on nonaromatic carbon; and
the R 12 rings are optionally additionally mono- or di-substituted independently with (C 1 -C 5 )alkyl or halo.
22 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (IV)
wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substituted by one or more of halo, nitro, cyano, lower alkyl, lower alkoxy or perhalo(lower)alkyl;
Y is CH or N;
either one of A, B and C is oxygen and the remaining two of A, B and C are CH 2 ; or A is oxygen, B is CH 2 , and C is a direct bond;
Q is:
W is —NR 5 —, —O—, or —S(O) n —;
X is —NO 2 , —P—NR 6 R 7 ,
Ar, OR 3 or halogen;
P is a direct bond, —CHR 11 — or —CHR 11 CHR 12 —;
R 1 , R 8 , R 9 and R 10 are independently hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups;
R 2 , R 4 , R 11 , R 12 and R 14 are hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups;
R 3 and R 13 are independently hydrogen, lower alkyl, (C 2 -C 8 ) perhaloalkanoyl or (C 2 -C 8 ) alkanoyl;
R 6 and R 7 are independently hydrogen, lower alkyl, phenyl or phenyl substituted by one or more of halo, perhalo(lower)alkyl, (C 2 -C 8 )alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy groups, lower alkoxy, or 2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R 6 and R 7 taken together with the nitrogen atom in NR 6 R 7 form unsubstituted or substituted 5- or 6-membered heterocyclyl ring systems containing carbon and one to four heteroatoms chosen from N, O and S, the heterocyclyl substituents being (C 1 -C 8 )alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted lower alkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, (C 2 -C 8 ) alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy group, lower alkoxy, 1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or a substituent represented by the formula:
R 5 is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, lower alkoxy, nitro, cyano, (C 2 —C)alkanoyl;
p is 0, 1, 2, 3, 4 or 5;
n is 0, 1 or 2;
r is 1 or 2; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, ester, or ether thereof.
23 . The method of claim 22 , wherein the CYP51A1 inhibitor is a compound represented by formula (V)
wherein Y and Ar are as defined for formula (IV);
one of A, B or C is oxygen and the remaining two of A, B, or C are —CH 2 —;
T is ═O, ═NOR 1 , ═NNR 1 R 2 or
wherein R 1 is hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups; and
R 2 is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups.
24 . The method of claim 22 , wherein the CYP51A1 inhibitor is a compound represented by formula (VI)
wherein Y, Ar, R 1 , R 2 , R 6 and R 7 are as defined for formula (IV), and either one of A, B and C is oxygen and the remaining two of A, B and C are CH 2 , or A is oxygen, B is CH 2 , and C is a direct bond.
25 . The method of claim 24 , wherein NR 6 R 7 is:
wherein Z is hydrogen, (C 1 -C 8 ) alkanoyl, lower alkyl, (C 1 -C 8 ) perhaloalkanoyl or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4-triazol-4-yl.
26 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (VII)
wherein one of A, B and C is oxygen and the remaining two of A, B and C are —CH 2 —, or two of A, B and C are —CH 2 —;
each Hal is independently Cl or F; and
Z is lower alkyl, (C 2 -C 8 )alkanoyl, or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4triazol-4-yl.
27 . The method of claim 26 , wherein the CYP51A1 inhibitor is selected from:
28 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (VIII)
wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substituted by one or more of halo, nitro, cyano, lower alkyl, lower alkoxy or perhalo(lower)alkyl;
Q is:
W is —NR 5 —, —O—, or —S(O) n —;
X is —NO 2 , —P—NR 6 R 7 ,
Ar, OR 3 or halogen;
P is a direct bond, —CHR 11 — or —CHR 11 CHR 12 —;
R 8 , R 9 and R 10 are independently hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups;
R 4 , R 11 , R 12 and R 14 are hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups;
R 3 and R 13 are independently hydrogen, lower alkyl, (C 2 -C 8 ) perhaloalkanoyl or (C 2 -C 8 ) alkanoyl;
R 6 and R 7 are independently hydrogen, lower alkyl, phenyl or phenyl substituted by one or more of halo, perhalo(lower)alkyl, (C 2 -C 8 )alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy groups, lower alkoxy, or 2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R 6 and R 7 taken together with the nitrogen atom in NR 6 R 7 form unsubstituted or substituted 5- or 6-membered heterocyclyl ring systems containing carbon and one to four heteroatoms chosen from N, O and S, the heterocyclyl substituents being (C 1 -C 8 )alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted lower alkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, (C 2 -C 8 ) alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy group, lower alkoxy, 1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or a substituent represented by the formula:
R 5 is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, lower alkoxy, nitro, cyano, (C 2 -C 8 )alkanoyl;
p is 0, 1, 2, 3, 4 or 5;
n is 0, 1 or 2;
r is 1 or 2; and
t is 0, 1, 2 or 3;
R 1 is hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups; and
R 2 is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups.
29 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (IX)
Wherein each X is independently F or Cl;
R 1 is a straight or branched chain (C 3 to C 8 ) alkyl group optionally substituted by one or two hydroxy moieties or by one or two groups convertible in vivo into hydroxy moieties;
or a pharmaceutically acceptable salt, ester, or ether thereof.
30 . The method of claim 29 , wherein the CYP51A1 inhibitor is a compound represented by formula (X)
wherein each X is independently F or Cl; and
R 2 is H or (C 1 -C 3 ) alkyl and R 3 is (C 1 -C 3 ) alkyl optionally substituted by one hydroxy moiety or by a group convertible in vivo into a hydroxy moiety;
or a pharmaceutically acceptable salt, ester, or ether thereof.
31 . The method of claim 30 , wherein the CYP51A1 inhibitor is a compound represented by formula (XI)
wherein R 5 is:
or a pharmaceutically acceptable salt, ester, or ether thereof.
32 . The method of claim 31 , wherein the CYP51A1 inhibitor is a compound represented by formula (XII)
wherein R 9 is —H(C 2 H 5 )CH(R 6 )CH 3 or —H(CH 3 )CH(R 6 )CH 3 ;
R 6 is OH or a group convertible in vivo into OH;
or a pharmaceutically acceptable salt, ester, or ether thereof.
33 . The method of claim 29 , wherein the CYP51A1 inhibitor is:
or a pharmaceutically acceptable salt, ester, or ether thereof.
34 . The method of any one of claims 29 - 33 , wherein the CYP51A1 inhibitor is an ester of the indicated compound.
35 . The method of claim 34 , wherein the ester is a phosphate ester.
36 . The method of claim 35 , wherein the phosphate ester is selected from
wherein z is 0 or 1, R 7 is a (C 1 -C 6 ) straight or branched chain alkyl group or H, f and n are independently an integer from 0 to 6, m is zero or 1 and W is H, CH 2 Ar or and Ar is phenyl, phenyl substituted by halo, nitro, cyano or trihalomethyl.
37 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XIII)
wherein R O is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl-alkyl in which the cycloalkyl is of 3 to 6 carbon atoms and the alkyl portion of 1 to 3 carbon atoms, the cycloalkyl and cycloalkyl-alkyl being optionally ring substituted by one or two alkyl groups of 1 to 3 carbon atoms;
R is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or nitro;
R′ is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, —CF 3 in the 3-position of Ring A, nitro, —CN, —COOR″, an optionally substituted phenyl group of the formula:
or an optionally substituted phenoxy group in the 4-position of Ring A and having the formula:
R″ is hydrogen, alkyl of 1 to 4 carbon atoms or a cation, preferably an agriculturally acceptable cation, or R and R′ together represent alkylenedioxy of 1 or 2 carbon atoms substituted onto adjacent carbon atoms of the phenyl Ring A; and
Y O and Y are independently hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
38 . The method of claim 13 , wherein the CYP51A1 inhibitor is an α-[aryl(alkylene) m ]-α-[CR 1 R 2 —(CHR 3 ) n —R 4 ]1 H-1,2,4-triazole-1-ethanol or an α-[aryl(alkylene) m ]-α-[CR 1 R 2 —(CHR 3 ) n —R 4 ]1 H-imidazole-1-ethanol, or a pharmaceutically acceptable salt or ester thereof, wherein:
R 1 is C 1-5 alkyl, unsubstituted or substituted by halogen, by C 1-5 -alkoxy, by phenyl-C 1-3 alkoxy, by phenoxy, by C 1-5 alkylthio, by phenyl-C 1-3 alkylthio or by phenylthio, whereby optional phenyl groups may be substituted by C 1-5 alkyl, halogen, halogen substituted C 1-5 alkyl, C 1-5 alkoxy or halogen substituted C 1-5 alkoxy; or
is C 2-5 alkenyl or C 2-5 alkynyl, unsubstituted or substituted by halogen; or
is cycloalkyl, unsubstituted or substituted by C 1-5 alkyl; or
is phenyl, unsubstituted or substituted by substituents selected from the group consisting of halogen and C 1-5 alkyl;
R 2 and R 3 , independently, are H or have an R 1 significance, whereby R 1 and R 2 may be linked together to form a C 3-7 cycloalkyl group;
m is 0 or 1;
n is 0, 1 or 2; and
R 4 is C 3-7 cycloalkyl, unsubstituted or substituted by C 1-5 alkyl.
39 . The method of claim 38 , wherein the CYP51A1 inhibitor is a compound represented by formula (XV)
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n are as defined in claim 35 , R 8 is H or C 1-5 alkyl, and Y is CH or N;
or a pharmaceutically acceptable salt, ester, or ether thereof.
40 . The method of claim 39 , wherein the CYP51A1 inhibitor is a compound represented by formula (XVI)
wherein R 2 is hydrogen or optionally substituted alkyl, such as optionally substituted lower alkyl; and
R 5 and R 6 are each independently hydrogen or a halogen atom, such as chloro;
or a pharmaceutically acceptable salt, ester, or ether thereof.
41 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XVII)
wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and CF 3 ;
R 1 is C 1 -C 4 alkyl;
R 2 is H or C 1 -C 4 alkyl; and
“Het”, which is attached to the adjacent carbon atom by a ring carbon atom, is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. “Het” may be optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , CN, NO 2 , NH 2 , —NH(C 1 -C 4 alkanoyl) or —NHCO 2 (C 1 -C 4 alkyl);
or a pharmaceutically acceptable salt, ester, or ether thereof.
42 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XVIII)
wherein R is optionally substituted phenyl;
R 1 is optionally substituted alkyl, such as optionally substituted lower alkyl;
R 2 is H or optionally substituted alkyl, such as optionally substituted lower alkyl;
X is CH or N; and
Y is a halogen, such as F or C;
or a pharmaceutically acceptable salt, ester, or ether thereof.
43 . The method of claim 42 , wherein the CYP51A1 inhibitor is a compound represented by formula (XIX)
wherein R, R 1 , R 2 , X, and Y are as defined for formula (XVIII).
44 . The method of claim 42 , wherein the CYP51A1 inhibitor is a compound represented by formula (XX)
wherein R, R 1 , R 2 , X, and Y are as defined for formula (XVIII).
45 . The method of claim 42 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXI)
wherein R, R 1 , R 2 , X, and Y are as defined for formula (XVIII).
46 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXII)
wherein R 1 is an optionally substituted alkyl, cycloalkyl, aryl, or arylalkyl group; and
Y1 and Y 2 are each independently ═CH— or ═N—;
or a pharmaceutically acceptable salt, ester, or ether thereof.
47 . The method of claim 46 , wherein the CYP51A1 inhibitor is a compound selected from:
48 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXIII)
wherein each of R 1 , R 2 , and R 3 is independently an aryl group represented by the formula:
n is an integer of from 0 to 5 and each R′ is independently halogen or optionally substituted alkyl; and
each X is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl;
or a pharmaceutically acceptable salt thereof.
49 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXIV)
wherein each of R, R 1 , and R 2 is independently hydrogen, optionally substituted alkyl, or optionally substituted aryl;
each of X, X′, and X′″ is independently hydrogen, halogen, optionally substituted alkyl or optionally substituted aryl; and
each of n, n′, and n″ is independently an integer of from 1 to 5.
50 . The method of claim 49 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXV)
wherein X, X′, X′″, n, n′, and n″ are as defined for formula (XXIV).
51 . The method of claim 50 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXVI)
wherein X, X′, X′″, n, n′, and n″ are as defined for formula (XXIV).
52 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXVII)
wherein A and B are independently selected from optionally substituted alkyl, optionally substituted naphthyl, optionally substituted biphenyl, and optionally substituted phenyl, and Z is CH or N.
53 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXVIII)
wherein R is optionally substituted aryl, such as phenyl, pyridyl, tetrahydropyranyl, norbornyl, C 3 -C 12 cycloalkyl or C 5 -C 8 cycloalkenyl, each of which may be unsubstituted or monosubstituted to trisubstituted by halogen, nitro, phenoxy, alkyl, amino, alkoxy, haloalkoxy, or haloalkyl;
each X is independently fluorine, chlorine, bromine, or iodine; and
each n is independently an integer of from 1 to 5.
54 . The method of claim 53 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXIX)
wherein R and X are as defined for formula (XXVIII).
55 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXI)
wherein each of rings A and B are independently optionally substituted and optionally fused aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
each X is independently halogen or optionally substituted alkyl; and
n is an integer of from 1 to 5.
56 . The method of claim 55 , wherein CYP51A1 inhibitor is a compound represented by formula (XXXII)
wherein each X is independently halogen or optionally substituted alkyl; and
each n is independently an integer of from 1 to 5.
57 . The method of claim 56 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXIII)
wherein each X and n are as defined for formula (XXXII).
58 . The method of claim 57 , wherein CYP51A1 inhibitor is:
59 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXIV)
wherein each X is independently halogen or optionally substituted alkyl; and
each n is independently an integer of from 1 to 5.
60 . The method of claim 59 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXV)
wherein each X and n are as defined for formula (XXXIV).
61 . The method of claim 60 , wherein the CYP51A1 inhibitor is:
62 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXVI)
wherein Q is selected from the group consisting of CH and N;
Ar is an optionally substituted, optionally fused aryl group, such as an optionally fused, optionally substituted phenyl group, for example, a phenyl group having from 1 to 3 substituents, such as from 1 to 3 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy;
A is selected from the group consisting of:
(a) an isothiocyanato group —N═C═S;
(b) an amino group of the formula
wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen and lower alkyl;
(c) a group of the formula
wherein X is selected from the group consisting of O and S, Y is selected from the group consisting of O and NH, m is the integer 0 or 1, and R 3 is selected from the group consisting of hydrogen, lower alkyl, mono- and dihalo-(lower alkyl), phenyl and substituted phenyl, said substituted phenyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy, optionally provided that:
i) when said X is S, then said Y is NH and said m is 1; and
ii) when said Y is O and said m is 1, then said R 3 is other than hydrogen; and
(d) a group of the formula
wherein Z is selected from the group consisting of a direct bond, CH 2 , O and N—R 4 , wherein R 4 is selected from the group consisting of hydrogen, lower alkyl, hydroxy-(lower alkyl), (lower alkyloxy)-lower alkyl, lower alkanoyl, lower alkylsulfonyl, phenylmethylsulfonyl, lower alkyloxycarbonyl, lower alkyloxycarbonylmethyl, phenoxycarbonyl, aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, aminocarbonylmethyl, (lower alkyl)aminocarbonylmethyl, (lower alkyl)aminothioxomethyl, (lower alkylthio)thioxomethyl, phenyl, phenylmethyl, benzoyl and substituted benzoyl, said substituted benzoyl being benzoyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy; and R is selected from the group consisting of hydrogen and nitro, optionally provided that when said R is nitro, then said A is amino.
63 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXVII)
wherein Q is selected from the group consisting of N and CH;
Ar is selected from the group consisting of phenyl, thienyl, halothienyl and substituted phenyl, the substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of halo, lower alkyl, lower alkyloxy and trifluoromethyl; and
the group Y is selected from the group consisting of:
a group of the formula —SO 2 R 1 , wherein R 1 is selected from the group consisting of trifluoromethyl and aryl;
a group of formula -alk-R 2 , wherein alk is selected from the group consisting of lower alkylene and lower alkenylene and R 2 is selected from the group consisting of cyano, amino, mono- and di(lower alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl, aryloxy and aryl, provided that alk is other than methylene when R 2 is phenyl;
a group of formula
wherein n is an integer of from 0 to 6 inclusive, X is O or S and R 3 is selected from the group consisting of hydrogen, mono-, di- and trihalolower alkyl, amino, mono- and di(lower alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino, aminolower alkyl, mono- and di(lower alkyl)aminolower alkyl, (1-pyrrolidinyl)lower alkyl, (1-morpholinyl)lower alkyl, (1-piperidinyl)lower alkyl, aryl, aryllower alkyl, aryllower alkenyl and lower alkyloxycarbonyllower alkyloxy, optionally provided that:
(i) said n is other than 0 or 1 when said R 3 is amino or lower alkylamino; and
(ii) said n is other than 0 when said R 3 is di(lower alkyl)amino or aryl; and
a group of formula
wherein m is an integer of from 1 to 6 inclusive, A is O or NH, X is O or S and R 4 is selected from the group consisting of hydrogen, lower alkyl, lower alkyloxy, aryl, aryloxy, aryllower alkyl, amino, mono- and di(lower alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl and 1-piperidinyl;
wherein said aryl is selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, lower alkylthienyl and pyridinyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, amino, mono- and di(lower alkyl)amino, lower alkylcarbonylamino, nitro and trifluoromethyl.
64 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by (XXXVIII)
wherein X is oxygen or sulfur, R 1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl and R 2 is optionally substituted phenyl, phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl, provided that when R 1 is methyl or phenyl R 2 is substituted phenyl or optionally substituted phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl.
65 . The method of claim 64 , wherein X is selected from the group consisting of oxygen and sulfur, R 1 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 or 4 carbon atoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, optionally substituted phenyl, phenylalkyl, of the formula Ph(CH 2 ) n where n is 1 to 5, phenylalkenyl of 9 to 11 carbon atoms, phenoxyalkyl of the formula PhO(CH 2 ) n where n is 2 to 5 and phenylthioalkyl of the formula PhS(CH 2 ) n where n is 2 to 5, wherein the substituted phenyl nucleus has at least one substituent selected from the group consisting of halo, alkoxy of 1 or 2 carbon atoms, alkyl of 1 to 4 carbon atoms, trihalomethyl, cyano, methylthio, nitro and methylsulphonyl, and R 2 is selected from the group consisting of optionally substituted phenylalkyl, of the formula Ph(CH 2 ) n where n is 1 to 5, phenylalkenyl of 9 to 11 carbon atoms, phenoxyalkyl of the formula PhO(CH 2 ) n where n is 2 to 5 and phenylthioalkyl of the formula PhS(CH 2 ) n where n is 2 to 5, wherein the substituted phenyl nucleus has at least one substituent selected from the group consisting of halo, alkoxy of 1 or 2 carbon atoms, alkyl of 1 to 4 carbon atoms, trihalomethyl, cyano, methylthio, nitro and methylsulphonyl.
66 . The method of claim 65 , wherein the CYP51A1 inhibitor is prochloraz.
67 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XXXIX)
wherein Z is an alkylene selected from the group consisting of —CH 2 CH 2 —, —CH 2 —CH 2 CH 2 —, —CH(CH 3 )CH(CH 3 )—, and —CH 2 CH(alkyl)-, wherein the alkyl has from 1 to about 10 carbon atoms; and
Ar is an optionally fused, optionally substituted aryl group, such as an optionally fused, optionally substituted phenyl, thienyl, naphthyl, or fluorenyl, for example, phenyl, thienyl, halothienyl, naphthyl and fluorenyl, each optionally containing one or more (e.g., from 1 to 3) substituents selected independently from the group consisting of halo, lower alkyl, lower alkyloxy, cyano, and nitro.
68 . The method of claim 67 , wherein the CYP51A1 inhibitor is propiconazole.
69 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XL)
wherein R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aroxyalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
X is —SH, —SR 3 , —SO—R 3 , —S 2 —R 3 , or —SO 3 H, wherein R 3 is alkyl which is optionally substituted by one or more halogen moieties (e.g., fluorine and/or chlorine), alkenyl which is optionally substituted by one or more halogen moieties (e.g., fluorine and/or chlorine), optionally substituted aralkyl or optionally substituted aryl.
70 . The method of claim 69 , wherein the CYP51A1 inhibitor is prothioconazole or prothioconazole-desthio.
71 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XLI)
wherein R 1 is —CH═CH—X, —C≡C—X, or —CH 2 —CH 2 —X, wherein X is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or optionally substituted aryl, aralkyl, aryloxy alkyl, or heterocycle;
R 2 is alkyl, cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl) or optionally substituted aryl;
Z is Cl, CN, or OR 3 , wherein R 3 is hydrogen, acetyl, alkyl, alkenyl or aralkyl; and
Y is ═N— or ═CH—,
or a pharmaceutically acceptable salt, ester, or ether thereof.
72 . The method of claim 71 , wherein the CYP51A1 inhibitor is tebuconazole.
73 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XLII)
wherein X 1 is hydrogen or an alkyl group,
X 2 is hydrogen or an alkyl group,
R 1 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionally substituted aryl or aralkyl group,
R 2 is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionally substituted aryl or aralkyl group,
R 3 is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionally substituted aryl or aralkyl group, and
Y is a keto group or a functional keto derivative.
or a pharmaceutically acceptable salt, ester, or ether thereof.
74 . The method of claim 73 , wherein the CYP51A1 inhibitor is triadimenol.
75 . The method of claim 13 , wherein the CYP51A1 inhibitor is a compound represented by formula (XLIII)
wherein n is 2 or 3;
p is 0, 1 or 2;
q is 0, 1 or 2;
X is oxygen or S(O) t wherein t is 0, 1, or 2;
each R 1 is independently halo, lower alkyl, lower alkoxy, or trifluoromethyl;
each R 2 is independently halo or lower alkyl;
R 3 is nitro or —N(R 5 )R 6 where
R 5 is hydrogen or lower alkyl;
R 6 is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R 7 where Y is oxygen or sulfur and R 7 is hydrogen, lower alkyl, lower alkoxy or —N(R 8 )R 9 where R 8 is hydrogen or lower alkyl and R 9 is hydrogen, lower alkyl or lower alkoxycarbonyl; or
R 5 and R 6 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by —C(O)R 10 where R 10 is hydrogen, lower alkyl, lower alkoxy or amino; and
R 4 is hydrogen or optionally substituted lower alkyl;
or a pharmaceutically acceptable salt, ester, or ether thereof.
76 . The method of claim 75 , wherein the compound represented by formula (XLIII) is a compound represented by formula (XLIV)
wherein R 1 , R 2 , R 3 , R 4 , X, n, p, and q are as defined for formula (XLIII).
77 . The method of claim 75 , wherein the compound represented by formula (XLIII) is a compound represented by formula (XLV)
wherein R 1 , R 2 , R 3 , R 4 , X, n, p, and q are as defined for formula (XLIII).
78 . The method of claim 75 , wherein the compound represented by formula (XLIII) is a compound represented by formula (XLVI)
wherein R 1 , R 2 , R 3 , R 4 , X, n, p, and q are as defined for formula (XLIII).
79 . The method of claim 75 , wherein the compound represented by formula (XLIII) is a compound represented by formula (XLVII)
wherein R 1 , R 2 , R 3 , R 4 , X, n, p, and q are as defined for formula (XLIII).
80 . The method of claim 75 , wherein the compound represented by formula (XLIII) is a compound represented by formula (XLVIII)
wherein R 1 , R 2 , R 3 , R 4 , X, n, p, and q are as defined for formula (XLIII).
81 . The method of claim 75 , wherein the CYP51A1 inhibitor is azalanstat.
82 . The method of claim 13 , wherein the CYP51A1 inhibitor is selected from the group consisting of LEK-935, CP-320626, itraconazole, posaconazole, cyproconazole, voriconazole, fluconazole, clotrimazol, fenticonazole, epoxiconazole, ketoconazole, ravuconazole, isavuconazole, holothurin A, theasaponin, capsicosine, betulafolientriol, prochloraz, propiconazole, prothioconazole, prothioconazole-desthio, tebuconazole, triadimenol, azalanstat, and variants thereof.
83 . The method of claim 13 , wherein the CYP51A1 inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to CYP51A1 and/or inhibits CYP51A1 catalytic activity.
84 . The method of claim 13 , wherein the CYP61A1 inhibitor is an interfering RNA molecule.
85 . The method of claim 84 , wherein the interfering RNA molecule is a short interfering RNA, micro RNA, or short hairpin RNA.
86 . The method of any one of claims 1 - 5 and 8 - 85 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis, and following the administration of the CYP51A1 inhibitor to the patient, the patient exhibits one or more, or all, of the following responses:
(i) an improvement in condition as assessed using the amyotrophic lateral sclerosis functional rating scale or the revised ALSFRS;
(ii) an increase in slow vital capacity;
(iii) a reduction in decremental responses exhibited by the patient upon repetitive nerve stimulation;
(iv) an improvement in muscle strength;
(v) an improvement in quality of life;
(vi) a decrease in the frequency and/or severity of muscle cramps; and/or
(vii) a decrease in TDP-43 aggregation.
87 . A kit comprising a CYP51A1 inhibitor and a package insert, wherein the package insert instructs a user of the kit to administer the CYP51A1 inhibitor to the patient in accordance with the method of any one of claims 1 - 5 and 8 - 85 .Cited by (0)
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