CA3062452A1 - Compositions, combinations, and methods thereof for treatment of neurological disorders - Google Patents
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Abstract
Description
WITH NOVEL COMPOSITIONS, COMBINATIONS, AND METHODS THEREOF
TECHNICAL FIELD
[001] This disclosure relates to Targeted Drug Rescue (TDR)Tm with novel compositions, combinations, therapeutic formulations, symptomatic and disease-modifying treatments, therapies, kits thereof, and methods thereof.
BACKGROUND
Diseases affecting the brain and central nervous system represent one of the largest global healthcare challenges and greatest medical needs due to the devastating personal and economic consequences for patients, caregivers and society. An estimated 55 million people worldwide suffer from neurodegenerative diseases with no currently approved disease-modifying therapies available. As modern therapeutic interventions increase life expectancy, the number of patients suffering from these diseases is expected to double every 20 years. Just nine of the most common neurological diseases such as Alzheimer's disease and other dementias, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and Parkinson's disease is staggering, totaling S789 billion in 2014 dollars, currently estimated at S818 billion, and estimated to be more than Si trillion by 2030. Total European 2010 cost of brain disorders was Ã798 billion, of which direct health care cost 37%, direct non-medical cost 23%, and indirect cost 40% (Oleson et al., The economic cost of brain disorders in Europe, EJN, 19, 1,155-162 (2012).
indications, regulators have addressed the persisting high medical need by opening up the range of approvable medications to therapies with syndromal indication labels. Such a syndromal indication label could cover, e.g., Behavioral and Psychiatric Symptoms in Dementia (BPSD), sub-syndromal indications like aggression or apathy in Alzheimer's Disease, hallucinations and delusions in Parkinson's Disease Dementia (PDD). Accordingly, there is need for development of such new therapies with syndromal indication labels for novel compositions, combinations, therapeutic formulations, symptomatic and disease-modifying treatments, and therapies using EXCIVA TDRTm technology.
SUMMARY OF THE INVENTION
R; (cH2)õ
Formula I, wherein, Ri and R2 are independently H, substituted or unsubstituted C1_10 alkyl, substituted or unsubstituted C5_10 aryl, substituted or unsubstituted C3_10cycloalkyl-05_1() aryl, substituted or unsubstituted C4_10 bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-Cs_io aryl, substituted or unsubstituted C4_10 bicycloalkyl-Cs_io heteroaryl, substituted or unsubstituted C4-10 tricycloalkyl, substituted or unsubstituted C4_10 tricycloalkyl-Cs_io aryl, substituted or unsubstituted C4_10 tricycloalkyl-Cs_io heteroaryl, or substituted or unsubstituted C5_10 heteroaryl, or Ri and R2 together with the nitrogen form a saturated or unsaturated heterocycle having one or more hetero atoms selected from N, 0, and S;
R3 is independently H, substituted or unsubstituted Ci_io alkyl, substituted or unsubstituted Cs_io aryl, substituted or unsubstituted C5_10 heteroaryl, substituted or unsubstituted C3-10 cycloalkyl-io aryl, substituted or unsubstituted C4-10 bicycloalkyl, substituted or unsubstituted C4-io bicycloalkyl-Cs_io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Cs_io heteroaryl, substituted or unsubstituted C4_10 bicycloalkyl-Ci_io-alkyl-Cs_io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Ci_io-alkyl-Cs_ioheteroaryl, substituted or unsubstituted C4_10 tricycloalkyl, substituted or unsubstituted C4_iotricycloalkyl-Ci_io-alkyl-05-10 aryl, substituted or unsubstituted C4-io tricycloalkyl-Ci_io-alkyl-Cs_io heteroaryl, substituted or unsubstituted C4_10 tricycloalkyl-Cs_io aryl, substituted or unsubstituted C4_10 tricycloalkyl-Cs_io heteroaryl, or substituted or unsubstituted C5_ 10 heteroaryl, or substituted or unsubstituted C5-10 heteroaryl;
n is an integer from 0 to 5; R4 is H, NH-Rs, S-Rs, -OH, 0-R5, ¨CO-Rs, ¨0-CO-R5, or ¨00-0-R5, wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof.
0,R7 12'6 H
Formula II , wherein, R6, R7, and R8 are independently H, D, Ci_io-alkyl, halo Ci_io-alkyl wherein halogen is F, Cl, or Br; R9 and Rio are independently H; Ci_io-alkyl;
halo Ci_io-alkyl wherein halogen is F, Cl, or Br; OH; or R9 and Rio together form a five-membered heterocycle wherein the hetero atom is 0, S, or N; enantiomers, metabolites, derivatives, prodrugs, salts, diastereomers, pharmaceutically acceptable salts, or N-oxides thereof, or a combination thereof; or 3) a combination of 1 and 2; or a combinations thereof.
receptor antagonist /inverse agonist, and CYP2D6 inhibitor. In another embodiment, the agent is an agent having properties of both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor. In another embodiment, the agent is a dual agent (DA) having properties of both 5-HT2A
receptor inverse agonist and CYP2D6 inhibitor. In another embodiment, the DA is a compound of Formula I.
BRIEF DESCRIPTION OF FIGURES
Aggression Domain Scores by Stage and Visit for Patients Included in the Sequential Parallel Comparison Design and 10-Week Analyses. A, Stage 1 (weeks 1-5); B, stage 2 (weeks 6-10) for placebo nonresponders rerandomized after stage 1; C, 10-week results (the 10-week secondary analysis includes only patients who continued the same treatment assignment throughout study participation; ie, were randomized to receive only dextromethorphan-quinidine or only placebo [excludes patients who were rerandomized from placebo to dextromethorphan-quinidine in stage 21, thus simulating a parallel-group design). Analysis-of-covariance models with treatment as fixed effect and baseline as covariate were used to compare mean change from baseline between groups at each time point. Baseline for stage 2 is the patients' scores at the start of stage 2. Least squares mean treatment differences are as follows: for stage 1, week 1, ¨0.8 (95%CI, ¨1.5 to ¨0.03; P =
.04), week 3, ¨1.0 (95%CI, ¨1.8 to ¨0.2; P = .01), and week 5, ¨1.5 (95%CI, ¨2.3 to ¨0.7; P <
.001); for stage 2, week 6, 0.7 (95%CI, ¨0.4 to 1.9; P = .19), week 8, ¨0.1 (95%CI, ¨1.3 to 1.2; P
= .93), and week 10, ¨1.6 (95%CI, ¨2.9 to ¨0.3; P = .02); for 10-week analysis, week 1, ¨0.9 (95%CI, ¨1.8 to ¨0.04; P = .047), week 3, ¨1.3 (95%CI, ¨2.2 to ¨0.3; P = .01), week 5, ¨1.8 (95%CI, ¨2.7 to ¨0.9; P <.001), week 6, ¨0.9 (95%CI, ¨2.0 to 0.1; P = .06), week 8, ¨1.3 (95%CI, ¨2.4 to ¨0.3; P = .01), and week 10, ¨1.8 (95%CI, ¨2.8 to ¨0.7; P = .003). a Observed cases (Cummings et al., Effect of dextromethorphan quinidine on agitation in patients with Alzheimer Disease dementia: a randomized clinical trial. JAMA 314(12):1242-1254 (2015), incorporated in entirety by reference).
(C) CGI-improvement scores. SAPS=scale for assessment of positive symptoms.
CGI=clinical global impression (Cummings et al., Pimavanserin for patients with Parkinson's disease psychosis:
a randomized, placebo-controlled phase 3 trial. Lancet, 383(9916):533-40 (8 February 2014), incorporated in entirety by reference).
Recombinant CYP2D6 was incubated with (A) 342-(N,N-Diethyl-N-methylammonium) ethy11-7-methoxy-4-methylcoumarin (AMMC) in the presence of CBD (FIGURE 4A), (B) dextromethorphan in the presence of CBD (FIGURE 4B), and (C) in the absence of CBD
(FIGURE 4C), HLMs were incubated with dextromethorphan in the presence or absence of CBD. Each point is the mean of duplicate determinations.
4E) in the presence of various amounts of A9-THC, CBD, and CBN; and (F) HLMs were incubated with 4 pM dextromethorphan in the presence of various amounts of A9-THC, CBD, and CBN (FIGURE 4F). Each point is the mean of two determinations (Yamaori et al., Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6, Drug Metabolism and Disposition, Vol. 39, No. 11(2011) incorporated in entirety by reference).
Data are presented as mean ( SD) concentration (ng/ml). N=4.
n=16) once daily.
lower panel). N=6.
N=4.
DETAILED DESCRIPTION OF THE INVENTION
62/636,171 filed 02/22/2018, US 62/635,554 filed 02/27/2018, and US 62/636,099 filed 02/27/2018, all of which are incorporated by reference.
Rf Formula I/ wherein, Ri and R2 are independently H, substituted or unsubstituted C1_10 alkyl, substituted or unsubstituted C5_10 aryl, substituted or unsubstituted C3_10 cycloalkyl-05_10 aryl, substituted or unsubstituted C4_10bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-05_10 aryl, substituted or unsubstituted C4_10bicycloalkyl-05_10heteroaryl, or substituted or unsubstituted C5-10heteroaryl, or Ri and R2 together with the nitrogen form a saturated or unsaturated heterocycle having one or more hetero atoms selected from N, 0, and S;
R3 is independently H, substituted or unsubstituted C1_10 alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C5_10 heteroaryl, substituted or unsubstituted C3-10 cycloalkyl-Cs_ io aryl, substituted or unsubstituted C4-10 bicycloalkyl, substituted or unsubstituted C4_io bicycloalkyl-C10 aryl, substituted or unsubstituted C4_10 bicycloalkyl-C10 heteroaryl or substituted or unsubstituted C5-10 heteroaryl; n is an integer from 0 to 5; R4 is H, NH-Rs, S-Rs, -OH, 0-R5, ¨CO-Rs, ¨0-CO-R5, or ¨00-0-R5, wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof.
Ci_10-alkyl; halo C1_10-alkyl wherein halogen is F, Cl, or Br; OH; or R9 and Rio together form a five-membered heterocycle wherein the hetero atom is 0, S, or N.
.1414(48 7-a Formula In Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Compound 15 Compound 16 Compound 17 Pure Enantmmor (4_8)YQ1(1_81)_TIS- (3)5)11 (4F3)-(1D'T (4sY-A4 õ,*2 FZ-(3115 Formula lb Compound 18 Compound 19 compound 20 Compound 21 Compound 22 Compound 23 Compound 24 Pure Tnantiorner
is ethyl, and R4 is OH. In another embodiment, the heterocycle is a five-membered ring. Another embodiment is where the heterocycle is a six-membered ring. In another embodiment, the heterocycle is saturated.
Another embodiment has the unsaturated heterocycle. In one embodiment the heterocycle has one hetero atom. In another, the heterocycle has two hetero atoms.
(73 (7) (7) (7) (7) (7) (7)
An embodiment of the invention is a composition comprising a compound of formula I and dextromethorphan. An embodiment of the invention is a composition comprising a compound of formula I and DEX-H3, DEX-D3, DO, or DO-D3. An embodiment of the invention is a composition comprising: Ml, Ml-El, Ml-E2, SGL, SGL-El, or SGL-E2; and DEX-H3, DEX-D3, DO, or DO-D3.
)\I, Ri (012)n 770, the Formula I: Formula i, wherein R3 is a bicyclic system and the rest of the Formula I
represented by R7: as shown in Formula If 7 Formula If, wherein, R6 is H, substituted or unsubstituted -C1_10 alkyl, substituted or unsubstituted -C3_10 cycloalkyl, substituted or unsubstituted -05_10 aryl, substituted or unsubstituted -C1_10 alkyl- C5_10 aryl, substituted or unsubstituted -05_10 heteroaryl, or substituted or unsubstituted -C1_10 alkyl- C5_10 heteroaryl;
I
R7 is ' ¨, -Ci_ioalkyl-X-(Y)., -C3_10 cycloalkyl-X-(Y)m, -05_10 aryl-X-(Y)m, or -05_10 heteroaryl-X-(Y)m; wherein X is a bond, N, 0, S, -C1_10 alkyl, -C3_10 cycloalkyl, -05_10 aryl, -CO-Ci_io alkyl, -CO- C3_10 cycloalkyl, -0005_10 aryl, -CO-05_10 heteroaryl, -CO-NH-C1_10 alkyl, -CO-NH-C3_10 cycloalkyl, -CO-NH- C5_10 aryl, or -CO-NH-05_10 heteroaryl; Y is H, Ci_io alkyl, C3-10 cycloalkyl, C5_10 aryl, -CO-C1_10 alkyl, -CO- C3-10 cycloalkyl, -0005_10 aryl, CO-05_10 heteroaryl, -CO-NH-C1_10 alkyl, -CO-NH-C3-10 cycloalkyl, -CO-NH- C5_10 aryl, or -CO-NH-05_10 heteroaryl;
and m is an integer 1 or 2; or pharmaceutically acceptable salts or N-oxides thereof; or prodrugs thereof.
and DEX-H3, DEX-D3, DO, or DO-D3.
(Compounds 44-46), Maleic Acid HO2C-CH=CH-CO2H (Compounds 47-49), Succinic Acid HO2C-(CH2)2-CO2H (Compounds 50-52), Glutaric acid HO2C-(CH2)3-CO2H (Compounds 53-55), Adipic Acid HO2C-(CH2)4-CO2H (Compounds 56-58), Pimelic acid HO2C-(CH2)5-CO2H
(Compounds 59-61), Sebacic acid HO2C-(CH2)6-CO2H (Compounds 62-64), Formic acid HCO2H
(Compounds 65-67), Acetic acid CH3CO2H (Compounds 68-70), Propionic acid (Compounds 71-73), Butyric acid CH3(CH2)2CO2H (Compounds 74-76), Valeric acid CH3(CH2)3CO2H (Compounds 77-79), Caproic acid CH3(CH2)4CO2H (Compounds 80-82), Enanthic acid CH3(CH2)5CO2H (Compounds 83-85), Caprylic acid CH3(CH2)6CO2H
(Compounds 86-88), Pelargonic acid CH3(CH2)7CO2H (Compounds 89-91), Capric acid CH3(CH2)8CO2H
(Compounds 92-94), Oxalic Acid HO-CO-CO2H (Compounds 95-97), Isophthallic Acid C6H4(CO2H)2 (Compounds 98-100), Terephthallic Acid C6H4(CO2H)2 (Compounds 101-103), Salicylic Acid HO-C6H4-CO2H (Compounds 104-106), Acetyl Salicylic Acid CH3-00-CO2H (Compounds 107-109).
compounds 25-29.
An embodiment of the invention is a compound of formula I, wherein the compound is sarpomethionate, wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is methionate; compounds 30-34. An embodiment of the invention is a compound of formula I, wherein the compound is sarpophthallate, wherein R1, R2, and R3 are methyl, X is ethyl, and R4 is phthalate; compounds 35-37. An embodiment of the invention is a compound of formula I, wherein the compound is sarpomalonate, wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is malonate' compounds 38-40. An embodiment of the invention is a compound of formula I, wherein the compound is sarpotyrosinate, wherein R1, R2, and R3 are methyl, X is ethyl, and R4 is tyrosinate; compounds 41-43. An embodiment of the invention is a compound of formula I, wherein the compound is sarpotryptophanate, wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is tryptophanate;
compounds 44-46. In an embodiment, the composition is a combination of DEX and at least one compound selected from compounds 10-46, SGL, SGL-E1, SGL-E2, Ml, MI-El, Ml-E2.
An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan.
N¨
compound OH V
Compound 26 Compound 27 \ \
N¨ 0 0 qb IN¨ 0 H
OH
Compound a cund 29 0 ompo0H \
N-HO)ft11) \ 0 Compound 20 /N
NH2 NH2 Compound 37 Compound I C 31 Compound 14 11 Compound 36 ¨ Compomd 35
An embodiment of the invention is a composition comprising a compound selected from the group consisting of SGL, enantiomers thereof, a metabolite thereof, Ml, SG1, SG2, SMG1, SMG2, SMG3, a derivative thereof, a prodrug thereof, and a combination thereof, and dextromethorphan.
1R-63' 38 39 40 41 Compound 42 oHdcy-0 b 811 HO
HO
Compound 43 Compound 44 45 .46 CES 1741, CE-41 13 -1 C 0 7H OH OH
47 Compound 48 Compound 49 Compound 50 Compound 52 Compound 53 C..P^u^d 4 Compound 55 Compound 56 57 58 59 60 61 62 Cnop..d 63 64 .41 d ¨16Cd'- 11-4 9 -1 '31114:1 0 0 "
0 0 C)-0 C)-0 C)-0 0 C-C3 , Compouod 65 Compound 66 Compouod 67 Comp000d 68 CmnP000d 69 Compound 70 Compound 71 Compound 72 compound 73 Compound 74 Compound 75 :46_03 4c35-4=c33:1-,03- _ -4s35-Compouod 76 Compound 77 Compound 78 Compound 79 Compound 80 Compound 81 Compound 82 Compound 83 Compound 84 Compound 85 Compound 86 Compound 87 , = =
= . 4--_Vp 6=NIC-00 \
"Nr Y
-N---i r\ . 0100 0 011 O011 Compound 88 Compound 89 Compound 90 Compound 91 Compound 92 Compound 93 Compound 94 Compound 95 Compound 96 Compound 97 Compound 104 h", 0 0 $1 Compound 98 Compound 99 Compound 100 Compound 101 Compound 102 Compound 103 Compound 105 Compound 106 Compound 107 Compound 108 Compound 109 0i) HO cil) 71) t-)3i7)_->-3 Hc HO
HO H0.3 HO.;ir HO-3: HOt0 H0.3,r HO-30p Ht) HOi)"
Compound 110 Compound 111 Compound 112 Compound 113 Compound 114 Compound 115 Compound 116 Compound 117 Compound 118 Compound 119 Compound120 Compound n n ,!cii },1'.> ..) B1,17) B:1,17) 1111D ilD Ei=1) Eili i=17) 114i) Hi:1D
Compound 122 Compound 123 Compound 124 Compound 125 Compound 126 Compound 127 Compound 128 Compound 129 Compound 130 Compound 131 Compound 132 Compound 133 H LOHip HcHOL/D 00., H11), C ) EINI:1) HNI4iib 1=1) ci=1)14lor%:3i) 1)::3LID 1.11D
Compound 134 Compound 135 Compound 136 Compound 137 Compound 138 Compound 139 Compound 140 Compound 141 Compound 142 Compound 143 Compound 144 Compound 145
H R R,.,-, R3,0 R3,0 R3,0 R3.0 0 R3'0 N 3'0 S
- L' R3.0 Q b (N) cd r(N) b rc b cs b oFixb cs) b N x r X N
)(' R D, L0,6 0,io D. >,,a D \,0,C5 IR.( '6 IR,( C)t zi'C) 1 -, 4 1 s4(0 ..4 Formula Ig Formula Ih R4 Formula II R
Formula lc Formula Id Formula le Formula If Formula Tj R3.0 R3.0 R3.0 R3.0 R3,0 R3,0 R3,0 R3,0 c0 1)) --NH i)) QS ei 11N-r ej,, Fii,n,i-9 Jo HII-S) 4p-r\JH nH
( x--rN X x)-) ( x'') N x (N X (N X
Xj)1 IR,O,(5 RO,Io R40,a RO,(5 RI IR,?,0,6 IR,?,0,6 Rot Formula lk Formula II Formula Im Formula In Formula lo Formula 1p Formula Jr Formula Is
and/or prehexiline, flecainide, quinidine, (R)-propaphenone, (S)-propaphenone, isoniazid, (R)fluoxetine, (S)fluoxetine, nefazodone, paroxetine, ketoconazole, chloroquine, oxamniquine, primaquine, quinine, acetbutolol, betaxolol, bufuralol, oxprenolol, pindolol, propranolol, budipine, simvastatin, fluvastatin, lovastatin, pravastatin, perazine, ajamlicine, corynanthine, lobeline, or derivatives thereof.
OH OH OH
IW 0, Compound 146 Compound 147 Compound Racemate M1 Enantiomer 1 (M1-E1) Enantiomer 2 (M1L-E2) (R)-1 -(dimethylamino)-3 -(2 -(3 -1-(dimethylamino)-3 -(2-(3 - (5)-1 -(dimethylamino)-3 -(243 - methoxyphenethyl)phenoxy)propan-2-ol methoxyphenethyl)phenoxy)propan-2-ol methoxyphenethyl)phenoxy)propan-2-ol cja e o o OH 0 )(.)LOH
'le Compound 50 Compound 51 Compound 52 Sarpogrelate Racemate (SGL) Sarpogrelate Enantiomer 1 (SGL-E1) Sarpogrelate Enantiomer 2 (SGL-E2) 44(1 -(dimethylamino)-3 -(243 - (5)-441 -(dimethylamino)-3 -(243 - (R)-441 -(dimethylamino)-3 -(243 -methoxyphenethyl)phenoxy)propa methoxyphenethyl)phenoxy)propan-methoxyphenethyl)phenoxy)propan-2-n-2-yl)oxy)-4-oxobutanoic acid 2-yl)oxy)-4-oxobutanoic acid yl)oxy)-4-oxobutanoic acid
Oz NO HC 0 .IL.00 z .r.j1... Hz60.x...,õ51...0 OzNO(HzC)20.r..,0 OzNO(Hze)30.10(-.._...Xo OzNO(HzC)40.r.,...-Zo 02No r-I-1 N'T-Lb kr-LI re-1 N'T-Lb ....k.
Compound 177 Compound 178 Compound 179 Compound 180 Compound 181 Compound 182 O OH OH 0 0 HO ') 01 0 1110 '''. 0 ON ¨0 Oh. 0 .....
..... A 4111... A' WO. 41.11111110. .111P.h.
.41/1.6. 0 7111111., H ,:, opp ..-N H H H op 0 H N, HH.,110 H N, HO
DEX-I I 3 DEX-D 3 I)0-H3 DO-D, Compound 154 Compound 155 Compound Compound 149 Compound 150 Compound 151 Compound 153 o lel 1 ___---Cr OHE5 CtP
H lug N\
¨
Ketamine Methadone Dextro-propoxyphene Ketobemidone IVIemantine lit line C0m1,0und 157Compound 159 Compound 160 Compound 161 Compound 162 Compound 898 Compound 899
. --:77,--/-4I
õ,¨/¨µ00 ....11000 ,, 0-,0, "FgDHF5\'=)H =:$'Fg:B F41i0
(222-225), difluoroacetic acid, HO2C-CF2H (226-228), and trifluoroacetic acid, HO2C-CF3 (229-231).
Compounds 201-203 \ Compounds 207-209 Corn ounds 216-218 Compounds 219-221 \c) Compounds 226-228 1FOH 1 \o% 1 FIF0 ¨N/
¨1\1/
S X crTho,FlOcr Ff b .r_be FF' r_bb F
Compounds 204-206 Compounds 210-212 Compounds 213-215 Compounds 222-224 Compounds 229-231
acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate glutarate, isophthallate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthallate, salicylate , sebacate, succinate, terephthallate, tyrosinate, tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-tyrosinate, N-acyl-tryptophanate, N-acyl-methionate, citrate, galactonate, glucaric acid (saccharic acid), mannonate, mucate, rhamnonate, and tartrate.
hydrogen acetate, hydrogen acetyl salicylate, hydrogen adipate, hydrogen aspartate, hydrogen butyrate, hydrogen caprate, hydrogen caproate, hydrogen caprylate, hydrogen enanthate, hydrogen formate, hydrogen fumarate, hydrogen glutamate, hydrogen glutarate, hydrogen isophthallate, hydrogen maleate, hydrogen malonate, hydrogen methionate, hydrogen oxalate, hydrogen pelargonate, hydrogen pimelate, hydrogen propionate, hydrogen phthallate, hydrogen salicylate , hydrogen sebacate, hydrogen succinate, hydrogen terephthallate, hydrogen tyrosinate, hydrogen tryptophanate, hydrogen valerate, hydrogen N-acyl-aspartate, hydrogen N-acyl-glutamate, hydrogen N-acyl-tyrosinate, hydrogen N-acyl-tryptophanate, hydrogen N-acyl-methionate, hydrogen citrate, hydrogen galactonate, hydrogen glucaric acid (saccharic acid), hydrogen mannonate, hydrogen mucate, hydrogen rhamnonate, and hydrogen tartrate.
..4E. JR) , F4.119F õ_......_.==== 101 o FI.N.,...0 7 0 4, F4,õ....m....õJt2.00, F --"10,^H. * 0 F54 5)5F F OH 4 0 f, F't1 r f1N HO FA FF1 Ft1F
Compound 231-233 Compound 234 236 F F
Cad 237-:
41 F 11i-j F * F7 ,r9 4 F7 *
N¨F1 N¨rF.T..T ci F OCF3 0F 3 0, 3 , Comp F , F
Compound 249 251 F Compound 252 4 F Compound L
255 7 F Compound 258-60 Fj.F Compound 261-3 F"1/4F Compound 264-6 F54 F
0 * , Ffl 1(la 0 F.,r1V,....-7,--0 * ,,,,r, ,....,:i_rFo, .
,, k.........r.F3 .,....._.r.õ3.9%)a A........s..c....õ09_00 F5.,,F, F OCF, '41 0 F
LF FAF FtF 4F , 11JF
Compound 267- Compound Compound 270-2 Compound 273-5 Compound 276-278 Compound 279-81 Compound 282-4 F.Ft. F F FZF 041- roe, M, .i. .......r.-- F--Ff-11----Th.,-,0 F1 i N %0717F31.1 41 FF. OCHF01"3 ,......--57, F
OCHF"jR,(10 F OCHF9Ja F OCRF3JZICI
F1%F ..1''' F%'14.rC40iF13 compo,, 285-7 F54 comp , 288-90 F11.F1 c.01õõ 291-3 F1)4 F54 compoõ 297 õ F54 Ft F
Cpd 294-96 Compound 500-2 1*
0 * , F>Ft F * FZT,..--F, F.õ...1Z15.......e-,-, 'N OC17;11(2/C1 'A OCE7F, 41 0 'IC-7HF, '191.1 0 FIN.- 1 ,-1%c87F * 0 F F OCH,J52.410 F OCH:IFC2,0, F+F Fl lF F'FI.F
AF
F
Compound 312-14 F-j41 Compound 318-20 F F
F A 0 304 .1. 1 10 FiA ocffiFC2...Ø F-TA oc;i)42,13.0 ¨ ocH2F vs. 0 A oc2C2...CL, -N ocH 2F
"..., A ociA) Sim F54 F 2F ;(5F1 F+F '111' win 0 4 4 2F T.
, 0* , F., 1,5re F
F F A
.90 0 r1/C Fr 'r11Y3 *1 41 0 FiN
r2CI(1),42/ray. F C111' 55)F
Compound 239-41 F)q Compound 342 4 FAF1 Compound 345-F Compound 348-350 FYq Compound 3M-353 F F Compouad 554-356 FIF
'N¨cciT, 411 -FT --cciT, Compound 357 359F t F Compound 360-362 F'ICF) 363-365 (11F
0",coja0,0,1W-CC- õ0 l'-t'k"-r -1CL r-r4"1"0-Cl`a,c, >I, H 0...õ..) OH
a 0 N -1.---\0-- '11--% Cs' 1.12W-Y---.0 y' ) (' H
'rii -crR,0 011 criCLO: H2 N yO
OH
cycy,11---,i 3):::),--------trrod --014pLXIN¨r)::::) (511-----14,---r:i KICI
cr I H
CI I CI H
cro, iw Ni Fri...,H Irjo..õ_rH H HHN , , ....r.:21, H H "cr lig,r/
)1ii ir*Sic H H
a Ckjo 4-,,,1 l''ac' 0-Citi -14,--0- --t04 µ9)" l-rcrii::) :-. 11"---C:fi ecr04-Zir -NNisil H 0,9 ic, 479481 OH
)... s-õy.,,,o)0,1 OH u ........itrojx.LI fly, --r-gl, 0 OH 482-484 485.487 488490 491-491 iczAØ_cLpzii i cr....,......17)._t 0.....ztr, ti-= op Hip jcro,,,,,J4T, cli ....õ....Ø0, OH H
c .r r -N H----Si.--;
/n ,....414 crizyNzi N.õ ,....õ...0,rastii tr. ,,,N....õ..Ø...i....,õ
Fli-i----):3-&-\-NNN iitiTh-0¨\_ N
c N,...1 H--iir 41,1-N H -1 CI,I'Cr OrY-Ni= L14'1^04-145' i'lIfrOCC) H OH 11 SyN) , jo....õ12)0105' Crs";11J
)Z1nc-hiji H
H 014 H ''.4-1.1--0-N
H OH
336-538 r-v 539-541 542-544 545-547 548-550 551-*----' 0 1 OH ii 1:1 jsirCi 411.11 .CrIV'.....).'jkr RIYr/'s,(PN TOCIN Cc7112.1j or,k- j<
HR ) 560-562 363-565 566-568 569-571 572-574 n'14 H
581-583 }Thl 0-0Lpli 575-577H
r.. = = H
(:)."
9:14"(ii-Cri\-1 '1.NiCti,of CI:0- '--MH fr.-6-''Crj() '6.4:13'0'T-Hid Hj.."
*H b 584-586 0-"( 601 ., . 605-607 eA 4 13- r3, ...o.trys. TA H
.. ... oz, ' .1( 01 ) N 0 OH el H 1:141 I CLC3I1 /40.9. )Tr;CC
6014.610HO
.
631 632-634 )_-635.a37 6-0 0,..I....0)0 655rd 6.6t0BH
cid_cry c.)ti...5. is OH
H H r-g-H
641-64 S' 644-646 647'649 1 'S'( `Øril./` 744/6 41,,,,,Z 114 FTC(C)11 \21õT C1 04'Y'CI14S IS
* InC 1 fs4-c¨i-b-ci H OH di el ()2j)..* 4 683-683 686.688 61H-691 Wr1:4 --So aNOD' ' 101 191-1,14,...--y-L,9CVH,...
. 0.J 713-713 illit692694 " 695-697 698-700 0 701- 707-709 710-712 , r 716-718 r 11,014,.,.02. ti,,,,,p- cro jli,v 0,0õ,unio (9,0_,6;
Hino-N-R2 60-0 Y
R(Na,60...0 Ht 722-724 725-727 719-721 777-774 Fonda k Womb W
0) PIM rlIMMIN/
WIN= &roma
=
(S) Compound 219 (S)-1-(Mmo1hylamino)-3-(2-(3- (R)-1-(dimethylammo) 3 (2-(3 (S) 3 (2 (3 melhoxyptnelhyl)pheaoxy) (R) 3.(2 (3 melhoxyphenethyl)pheaoxy)-mothoxyphonV-Voronoxy)propo melhoxyph7:1111V,),yhenoxy)pro aria oma:Lo .xy.v.rtip2
represented by R7: as shown in Formula If R7 Formula If, wherein, R6 is H, substituted or unsubstituted -C1_10 alkyl, substituted or unsubstituted -C3_10 cycloalkyl, substituted or unsubstituted -05_10 aryl, substituted or unsubstituted -C1_10 alkyl- C5_10 aryl, substituted or unsubstituted -05_10 heteroaryl, or substituted or unsubstituted -C1_10 alkyl- C5_10 heteroaryl;
R7 is -Ci_ioalkyl-X-(Y)., -C3_10 cycloalkyl-X-(Y)m, -05_10 aryl-X-(Y)m, or -05-io heteroaryl-X-(Y)m; wherein X is a bond, N, 0, S, -C1_10 alkyl, -C3_10 cycloalkyl, -05_10 aryl, -CO-Ci_io alkyl, -CO- C3-10 cycloalkyl, -0005_10 aryl, -CO-05_10 heteroaryl, -CO-NH-C11 alkyl, -CO-NH-C3_10 cycloalkyl, -CO-NH- C5-10 aryl, or -CO-NH-05_10 heteroaryl; Y is H, C1_1() alkyl, C3-10 cycloalkyl, C5_10 aryl, -CO-C140 alkyl, -CO- C3-10 cycloalkyl, -0005_10 aryl, CO-05_10 heteroaryl, -CO-NH-C1_1() alkyl, -CO-NH-C3_10 cycloalkyl, -CO-NH- C5-10 aryl, or -CO-NH-05_10 heteroaryl;
and m is an integer 1 or 2; or pharmaceutically acceptable salts or N-oxides thereof; or prodrugs thereof.
RS 4- ((4- (dimethylamino)- 1 - (2 - (3- methoxyphenethyl)phenoxy)butan-2 -yl) oxy)-3 ,3 -difluoro -4 -oxobutanoic acid; S 4- ((4 - (dimethylamino)- 1 - (2 - (3-methoxyphenethyl)phenoxy)butan-2- yl) oxy)-3 ,3 -difluoro- 4- oxobutanoic acid; R4- ((4 - (dimethylamino)- 1 -(2 - (3 -methoxyphenethyl) phenoxy)butan- 2- yl)oxy)-3 ,3- difluoro -4 -oxobutanoic acid; RS 4 - ((4 -(dimethylamino)- 1 - (2 - (3-methoxyphenethyl)phenoxy) butan-2-yl)oxy)-2,2- difluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)- 1 - (2- (3 - methoxyphenethyl)phenoxy)butan- 2- yl)oxy)-2 ,2-difluoro- 4-oxobutanoic acid; R4-((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-yl)oxy)-2,2-difluoro-4- oxobutanoic acid; RS4- ((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan- 2- yl)oxy)-2 ,2,3- trifluoro- 4- oxobutanoic acid; S 4- ((4-(dimethyl amino)- 1 - (2 - (3 -methoxyphenethyl)phenoxy) butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid;
R4-((4-(dimethylamino) - 1 - (2 - (3- methoxyphenethyl) phenoxy)butan-2 - yl) oxy)-2,2,3 -trifluoro -4 -oxobutanoic acid; RS4- ((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-yl)oxy)-2,3,3- trifluoro -4 - oxobutanoic acid; S 4 - ((4 - (dimethylamino) -1 - (2- (3 -methoxyphenethyl) phenoxy)butan- 2- yl)oxy)-2 ,3 ,3- trifluoro- 4- oxobutanoic acid; R4 - ((4 -(dimethyl amino)- 1 - (2 - (3 -methoxyphenethyl)phenoxy)butan- 2- yl) oxy)-2 ,3 ,3 -trifluoro -4 -oxobutanoic acid; RS4 - ((4-(dimethylamino)-1-(2-(3- methoxyphenethyl) phenoxy) butan-2-yl)oxy)-2,3-difluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3-difluoro-4-oxobutanoic acid;
R4- ((4 - (dimethylamino)- 1 - (2 - (3 -methoxyphenethyl) phenoxy)butan- 2- yl)oxy)-2 ,3- difluoro -4 -oxobutanoic acid; RS 4 - ((4 -(dimethylamino)- 1 - (2 - (3-methoxyphenethyl) phenoxy)butan-2-yl)oxy)-2,2,3,3-tetrafluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)- 1 - (2- (3 - methoxyphenethyl)phenoxy)butan- 2- yl)oxy)-2 ,2,3 ,3- tetrafluoro - 4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-y1) oxy)-2,2,3,3- tetrafluoro-4- oxobutanoic acid; RS5- ((4-(dimethylamino) -1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; .. S5 -((4-(dimethylamino) - 1 - (2- (3 -methoxyphenethyl) phenoxy)butan-2-yl)oxy) - 4,4- difluoro-5-oxopentanoic acid; R5- ((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy) butan-2-yl)oxy)-4,4- difluoro-5- oxopentanoic acid;
RS 5 - ((4 - (dimethylamino)- 1 - (2 - (3-methoxyphenethyl)phenoxy)butan- 2- yl) oxy)-4 ,4 - difluoro-5- oxopentanoic acid; S5-((4-(dimethylamino)- 1 - (2- (3 -methoxyphenethyl) phenoxy) butan- 2- yl)oxy) -4,4 -difluoro -5 -oxopentanoic acid; R5-((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy) butan-2-yl)oxy) -4,4- difluoro-5- oxopentanoic acid; RS5-((4- (dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy) butan-2-yl)oxy) -2,2-difluoro -5-oxopentanoic acid;
S5-((4-(dimethylamino)- 1 - (2- (3 -methoxyphenethyl) phenoxy) butan- 2- yl) oxy)-2,2 -difluoro -5 -oxopentanoic acid; R5-((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy) butan-2-y1) oxy) -2,2- difluoro-5- oxopentanoic acid; RS4- (dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-y1 2,2-difluoroacetate; S4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-y1 2,2-difluoroacetate;
R4-(dimethylamino)-1-(2-(3-methoxyphenethyl) phenoxy)butan-2-y1 2,2-difluoroacetate; RS4-(dimethylamino)-1-(2-(3-methoxyphenethyl) phenoxy)butan-2-y1 2,2,2-trifluoroacetate; S4-(dimethylamino)-1-(2-(3-methoxyphenethyl) phenoxy)butan-2-y1 2,2,2-trifluoroacetate; R4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-y1 2,2,2-trifluoroacetate; RS4-((difluoromethyl)(trifluoromethyl)amino)-1-(2-(3 -(trifluoromethoxy) phenethyl)phenoxy) butan-2-ol; S4-((difluoromethyl) (trifluoromethyl) amino) -1- (2- (3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-((difluoromethyl) (trifluoromethyl) amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan-2-ol; RS4-((fluoromethyl) (trifluoromethyl) amino)-1-(2-(3-(trifluoromethoxy) phenethyl)phenoxy)butan-2-ol; S4-((fluoromethyl) (trifluoromethyl) amino)-1-(2-(3-(trifluoromethoxy) phenethyl)phenoxy) butan-2-ol; R4-((fluoromethyl) (trifluoromethyl)amino) -1-(2-(3-(trifluoromethoxy) phenethyl)phenoxy)butan-2-ol; RS4- (methyl (trifluoromethyl) amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; S4-(methyl (trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl)phenoxy)butan-2-ol; R4-(methyl(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl)phenoxy)butan-2-ol; RS 4-((difluoromethyl) (methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; S4-((difluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; R4-((difluoromethyl) (methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl)phenoxy) butan-2-ol; RS4-((fluoromethyl) (methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; S4-((fluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan-2-ol; R4-((fluoromethyl) (methyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy) butan-2-ol; RS4- (dimethylamino) -1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol;
S4-(dimethylamino) -1-(2-(3 -(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; R4-(dimethylamino)- 1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; R Si- (2-(3-(difluoromethoxy) phenethyl) phenoxy) -4 - (dimethylamino) butan-2 -ol ; Si - (2- (3 -(difluoromethoxy)phenethyl)phenoxy) -4 -(dimethylamino)butan-2-ol ; R1-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-4-(dimethylamino)butan-2-ol; R54-(dimethylamino) -1-(2-(3-(fluoromethoxy) phenethyl) phenoxy) butan-2 -ol ; 54- (dimethyl amino)- 1 - (2- (3- (fluoromethoxy) phenethyl)phenoxy)butan-2-ol; R4-(dimethyl amino) - 1 - (2 - (3 -(fluoromethoxy)phenethyl)phenoxy)butan-2-ol; R53- (trifluoro methoxy) -4-(2-(3- (trifluoromethoxy) phenethyl) phenoxy)-N,N- bis (trifluoromethyl) butan-1-amine; S3 -(trifluoromethoxy) -4-(2-(3-(trifluoromethoxy) phenethyl)phenoxy) -N,N-bis (trifluoro methyl) butan- 1 - amine; R3 - (trifluorometho xy)- 4- (2 - (3 -(trifluoromethoxy)phenethyl) phenoxy) -N,N-bi s (trifluoromethyl)butan- 1-amine; RS N-(difluoromethyl)-3 -(trifluoromethoxy)-4- (2-(3 -(trifluoromethoxy)phenethyl)phenoxy)-N- (trifluoromethyl)butan- 1-amine; SN-(difluoromethyl)-3- (trifluoromethoxy)-4- (2- (3 -(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan- 1-amine; RN-(difluoromethyl)-3- (trifluoromethoxy)-4 -(2 -(3 -(trifluoromethoxy)phenethyl)phenoxy) -N- (trifluoromethyl)butan-1 - amine; RS N-(fluoromethyl)-3 -(trifluoromethoxy)-4 -(2 -(3- (trifluoro methoxy) phenethyl)phenoxy)-N-(trifluoromethyl)butan- 1-amine; SN-(fluoromethyl)-3-(trifluoro methoxy)-4- (2- (3 -(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1 - amine ; RN-(fluoro methyl) -3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoro methyl) butan-l-amine; RSN-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)-N- (trifluoromethyl)butan- 1 - amine ; S N-methyl-3 - (trifluoromethoxy)-4- (2- (3-(trifluoromethoxy) phenethyl)phenoxy)-N- (trifluoromethyl)butan- 1-amine; RN-methyl-3 -(trifluoromethoxy)- 4- (2- (3 -(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan- 1-amine; RS N-(difluoromethyl) -N-methyl-3-(trifluoromethoxy)-4-(2-(3 -(trifluoromethoxy) phenethyl)phenoxy)butan-1 - amine ; SN-(difluoromethyl)-N-methy1-3-(trifluoromethoxy)-4- (2 -(3-(trifluoromethoxy)phenethyl)phenoxy)butan- 1 - amine ; RN-(difluoromethyl)- N- methyl-3 -(trifluoro methoxy)-4- (2- (3-(trifluoromethoxy)phenethyl)phenoxy)butan-1 - amine ; RS N-(fluoromethyl)- N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy) phenethyl)phenoxy) butan-1 - amine ;
SN- (fluoromethyl)-N- methyl-3 - (trifluoromethoxy)-4 -(2- (3 -(trifluoromethoxy) phenethyl) phenoxy)butan-1 - amine ; RN- (fluoromethyl)-N- methyl-3 -(trifluoromethoxy)-4 -(2 -(3 -(trifluoromethoxy)phenethyl)phenoxy)butan- 1 - amine ; RS N,N-dimethy1-3 -(trifluoromethoxy)-4 -(2 -(3- (trifluoromethoxy)phenethyl)phenoxy)butan-1 - amine ; SN,N-dimethy1-3-(trifluoromethoxy) -4 -(2- (3 -(trifluoromethoxy)phenethyl)phenoxy)butan- 1-amine;
RN,N-dimethy1-3-(trifluoromethoxy) -4- (2 -(3- (trifluoromethoxy)phenethyl)phenoxy)butan-1 -amine ; RS 44243 -(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethy1-3- (trifluoromethoxy)butan- 1-amine; S 4 -(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethy1-3- (trifluoromethoxy)butan- 1-amine;
R4- (2-(3-(difluoromethoxy) phenethyl)phenoxy) -N,N-dimethy1-3-(trifluoromethoxy) butan-1-amine; RS4-(2-(3-(fluoromethoxy) phenethyl)phenoxy)-N,N-dimethy1-3-(trifluoromethoxy) butan-1 - amine ; S4 -(2- (3- (fluoromethoxy) phenethyl)phenoxy) -N,N-dimethy1-3-(trifluoromethoxy) butan-1 - amine ; R4- (2- (3 -(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-(trifluoromethoxy)butan- 1 - amine ; RS3-(difluoromethoxy)-4 -(2 -(3 -(trifluoromethoxy) phenethyl) phenoxy)-N,N-bis(trifluoromethyl)butan- 1-amine; S3-(difluoromethoxy) -4-(2-(3-(trifluoro methoxy) phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-l-amine; R3-(difluoromethoxy)-4- (2- (3- (trifluoromethoxy)phenethyl)phenoxy)-N,N-bis (trifluoromethyl)butan -1-amine;
RS3- (difluoromethoxy)-N- (difluoromethyl)-4 -(2- (3-(trifluoromethoxy)phenethyl) phenoxy)-N- (trifluoromethyl) butan- 1 - amine; S3- (difluoromethoxy)-N-(difluoromethyl) -4 - (2 - (3 -(trifluoromethoxy)phenethyl)phenoxy)-N- (trifluoromethyl)butan- 1-amine; R(-(difluoromethoxy) -N- (difluoromethyl)- 4- (2- (3- (trifluoromethoxy)phenethyl)phenoxy) -N-(trifluoromethyl)butan- 1 -amine ; RS3- (difluoromethoxy) -N- (fluoromethyl) - 4- (2- (3-(trifluoromethoxy)phenethyl)phenoxy) -N- (trifluoromethyl)butan- 1 - amine; S3-(difluoromethoxy)-N- (fluoromethyl) -4 - (2 - (3 -(trifluoromethoxy)phenethyl)phenoxy)-N- (trifluoromethyl)butan- 1-amine; R3-(difluoromethoxy) -N- (fluoromethyl)- 4- (2- (3- (trifluoromethoxy)phenethyl)phenoxy) -N-(trifluoromethyl)butan- 1 -amine ; RS3- (difluoromethoxy) -N-methyl-4-(2-(3 -(trifluoromethoxy)phenethyl) phenoxy)-N-(trifluoromethyl) butan- 1 - amine ; S3 - (difluoromethoxy) -N- methy1-4 - (2-(3- (trifluoromethoxy) phenethyl)phenoxy) -N- (trifluoromethyl) butan- 1 - amine; R3 -(difluoromethoxy) -N- methyl- 4 - (2 -(3 - (trifluoromethoxy)phenethyl)phenoxy) -N- (trifluoromethyl)butan- 1 -amine; RS3- (difluoro methoxy) - N- (difluoromethyl)-N-methyl- 4- (2- (3-(trifluoromethoxy)phenethyl)phenoxy)butan- 1 -amine; S3-(difluoromethoxy)-N- (difluoromethyl) -N-methyl -4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan- 1-amine; R3-(difluoromethoxy) -N- (difluoromethyl)-N-methy1-4-(2-(3 - (trifluoromethoxy)phenethyl)phenoxy)butan- 1 - amine; RS 3 -(difluoromethoxy) -N-(fluoromethyl) -N-methyl- 4- (2- (3 -(trifluoromethoxy)phenethyl)phenoxy)butan- 1 - amine; S 3-(difluoro methoxy) -N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl) phenoxy)butan-l-amine; R3-(difluoromethoxy) -N-(fluoromethyl)- N-methy1-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan-l-amine; RS3-(difluoromethoxy)-N,N-dimethy1-4-(2 - (3- (trifluoromethoxy)phenethyl)phenoxy)butan- 1 - amine ; S3 -(difluoromethoxy) -N, N-dimethy1-4- (2-(3- (trifluoromethoxy) phenethyl)phenoxy)butan- 1-amine; R3-(difluoromethoxy)-N,N-dimethy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan- 1 - amine ;
(difluoromethoxy) -4- (2- (3- (difluoromethoxy) phenethyl)phenoxy)-N,N-dimethylbutan- 1-amine S3- (difluoromethoxy) -4 - (2 - (3- (difluoromethoxy)phenethyl)phenoxy)-N, N-dimethylbutan- 1-amine; R3-(difluoromethoxy) -4-(2-(3-(difluoromethoxy) phenethyl)phenoxy) -N,N-dimethylbutan -1-amine; RS 3 - (difluoromethoxy)- 4- (2- (3 -(fluoromethoxy)phenethyl)phenoxy)-N,N- dimethylbutan- 1 - amine ;
S3- (difluoromethoxy)- 4- (2- (3 - (fluoromethoxy)phenethyl) phenoxy)- N,N-dimethyl butan- 1 - amine;
R3-(difluoromethoxy)-4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan- 1 - amine ; RS 3 -(fluoromethoxy)- 4- (2 - (3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis (trifluoromethyl)butan- 1 - amine ; S3- (fluoro methoxy) -4-(2- (3 - (trifluoromethoxy)phenethyl)phenoxy) -N, N-bis (trifluoromethyl)butan- 1 -amine; R3-(fluoromethoxy)- 4-(2-(3-(trifluoromethoxy) phenethyl)phenoxy) -N,N-bis (trifluoromethyl) butan- 1-amine; RSN-(difluoromethyl)-3-(fluoromethoxy)-4-(2-(3-(trifluoro methoxy) phenethyl)phenoxy)-N- (trifluoromethyl)butan- 1 - amine ; SN-(difluoromethyl) -3 - (fluoro methoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine;
RN-(difluoromethyl)-3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoro methyl) butan-1- amine;
RS3 -(fluoromethoxy)-N-(fluoromethyl)-4-(2-(3-(trifluoromethoxy) phenethyl)phenoxy)-N-(trifluoromethyl)butan- 1-amine; S3-(fluoromethoxy)-N-(fluoromethyl)-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; R3 -(fluoromethoxy)-N-(fluoromethyl)-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-l-amine; RS3-(fluoromethoxy)- N-methyl-4- (2-(3-(trifluoromethoxy) phenethyl) phenoxy)-N-(trifluoromethyl) butan-l-amine; S3-(fluoromethoxy)-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1- amine; R3 -(fluoromethoxy)-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine;
RSN-(difluoromethyl)-3 -(fluoromethoxy)-N-methyl-4-(2-(3 -(trifluoromethoxy)phenethyl) phenoxy)butan-1- amine; SN-(difluoromethyl)-3-(fluoromethoxy)- N-methy1-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan- 1-amine; RN-(difluoromethyl)-3 -(fluoromethoxy)-N-methy1-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)butan-l-amine; RS3 -(fluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; S3-(fluoromethoxy)-N-(fluoromethyl)-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy) butan-l-amine;
R3 -(fluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3 -(trifluoromethoxy) phenethyl) phenoxy) butan-l-amine; RS3-(fluoromethoxy) -N,N-dimethy1-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan-1- amine; S3-(fluoromethoxy)-N,N-dimethy1-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)butan-1- amine; R3 -(fluoromethoxy)-N,N-dimethy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-l-amine; RS4-(2-(3-(difluoromethoxy) phen ethyl) phenoxy)-3- (fluoromethoxy)-N,N-dimethylbutan-1- amine; S4-(2-(3-(difluoro methoxy) phenethyl)phenoxy)-3- (fluoromethoxy)- N,N-dimethyl butan-l-amine; R4-(2-(3-(difluoro methoxy) phenethyl) phenoxy)-3-(fluoromethoxy)-N,N-dimethylbutan-1- amine; RS3 -methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-l-amine; S3-methoxy -4-(2-(3-(trifluoromethoxy) phenethyl)phenoxy)-N,N-bis (trifluoromethyl)butan-1-amine;
R3 -methoxy-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl) butan-l-amine; RSN-(difluoromethyl) -3-methoxy-4-(2-(3- (trifluoromethoxy) phenethyl) phenoxy) -N-(trifluoromethyl)butan-l-amine; SN- (difluoromethyl) -3 -methoxy-4-(2-(3 -(trifluoromethoxy) phenethyl) phenoxy)-N-(trifluoromethyl)butan-l-amine; RN-(difluoromethyl)-3-methoxy-4-(2-(3- (trifluoromethoxy) phenethyl)phenoxy)-N-(trifluoromethyl)butan- 1-amine RSN- (fluoromethyl) -3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoro methyl) butan- 1-amine; SN-(fluoromethyl)- 3-methoxy-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)-N- (trifluoromethyl) butan-l-amine; RN-(fluoromethyl) -3 -methoxy-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)-N- (trifluoromethyl)butan-l-amine; RS3-methoxy-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; S3-methoxy-N-methy1-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine ;
R3 -methoxy-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoro methyl) butan-l-amine; RS4-(2-(3 -(difluoromethoxy)phenethyl)phenoxy)-3 -methoxy-N,N-dimethylbutan-1- amine; S4-(2-(3-(difluoromethoxy) phenethyl)phenoxy) -3 -methoxy-N,N-dimethylbutan-1- amine;
R4-(2-(3 -(difluoromethoxy)phenethyl)phenoxy)-3 -methoxy-N,N-dimethylbutan-1- amine; RSN-(fluoromethyl)-3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan-1- amine;
SN-(fluoromethyl)-3-methoxy-N-methyl-4-(2-(3 -(trifluoromethoxy)phenethyl)phenoxy)butan-l-amine; RN-(fluoromethyl)-3-methoxy-N-methyl-44243 -(trifluoromethoxy)phenethyl)phenoxy)butan-1- amine ; RS4-(2-(3-(difluoromethoxy) phen ethyl) phenoxy)-3-methoxy-N,N-dimethylbutan-1- amine; S4-(2-(3-(difluoromethoxy) phen ethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; R4-(2-(3-(difluoromethoxy) phenethyl) phen oxy)-3-methoxy-N,N-dimethylbutan-1- amine;
RS4-(2-(3-(fluoromethoxy) phen ethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; S4-(2-(3-(fluoromethoxy) phen ethyl) phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; R4-(2-(3-(fluoromethoxy) phenethyl) phenoxy) -3 -methoxy-N,N-dimethylbutan-l-amine ;RS4-(2-(3 (fluoromethoxy) phenethyl) phenoxy) -3 -methoxy-N,N- dimethylbutan-1- amine;
S4-(2-(3-(fluoromethoxy) phenethyl)phenoxy ) -3 -methoxy-N,N- dimethylbutan-l-amine; R4-(2-(3-(fluoromethoxy) phenethyl) phenoxy)-3-methoxy-N,N-dimethylbutan-1- amine ;RS1-(piperidin-1-y1)-3 -(m-toly1 oxy) propan-2-ol; S1-(piperidin-1-y1)-3-(m-tolyloxy)propan-2-ol; R1-(piperidin-1-y1)-3-(m-tolyloxy) propan-2-ol; RS1-(4-(3-methoxyphenyl)piperazin-l-y1)-3-phenoxypropan-2-ol S1-(4-(3- methoxyphenyl) piperazin-l-y1)-3- phenoxypropan-2-ol; R1-(4-(3-methoxyphenyl) piperazin -1-y1)-3- phenoxypropan-2-ol; RS1-(2,2,5 ,5 -tetramethy1-2,5 -dihydro-1H-pyrrol-1-y1)-3-(m-tolyloxy)propan-2-ol;S1-(2,2,5,5-tetramethy1-2,5-dihydro-1H-pyrrol-1-y1)-3-(m-tolyloxy) propan -2-01; R1-(2,2,5,5-tetramethy1-2,5-dihydro-1H-pyrrol-1-y1)-3-(m-tolyloxy) propan-2-ol;
RS1-morpholino-3-(m-tolyloxy)propan-2-ol; Sl-morpholino-3- (m-tolyloxy) propan-2-ol; R1-morpholino-3 -(m-tolyloxy)propan-2-ol;
R53,3'-(phenylazanediy1)bis (1-phenoxypropan-2-ol);
S3,3'-(phenylazanediy1)bis(1-phenoxypropan-2-ol); R3,3'-(phenylazanediy1) bis (1-phenoxypropan-2-ol); RS1-(2,2,5,5-tetramethylpyrrolidin-l-y1)-3-(m-tolyloxy)propan-2-ol; Sl-(2,2,5,5 -tetramethylpyrrolidin-l-y1)-3 -(m-tolyloxy)propan-2-ol;
R1-(2,2,5,5-tetramethyl pyrrolidine -1-y1)-3 -(m-tolyloxy) propan-2-ol; RS1-(tert-butylamino)-3 -(3 ,4-dimethylphenoxy) propan-2-ol; S1-(tert-butylamino)-3-(3,4-dimethylphenoxy)propan-2-ol; R1-(tert-butylamino)-3-(3,4-dimethylphenoxy) propan-2-ol; RS1-(4-(3-chlorophenyl) piperazin-l-y1)-3 -phenoxypropan-2-ol ; S1-(4-(3 -chlorophenyl) piperazin-l-y1)-3-phenoxypropan-2-ol; R1-(4-(3 -chlorophenyl) piperazin-l-y1) -3-phenoxypropan-2-ol; RS1-(dimethylamino)-3-(2-phenoxy phenoxy) propan-2-01; S1-(dimethylamino) -3 -(2-phenoxyphenoxy)propan-2-ol; R1-(dimethyl amino)-3-(2-phenoxy phenoxy) propan-2-ol; RS1-(pyrrolidin-l-y1)-3-(m-tolyloxy)propan-2-ol; S1-(pyrrolidin-l-y1)-3 -(m-tolyloxy)propan-2-ol; R1-(pyrrolidin-l-y1)-3-(m-tolyloxy)propan-2-ol; RS1-amino-3-(3,5-dimethylphenoxy)propan-2-ol; Sl- amino-3 -(3,5 -dimethylphenoxy)propan-2-ol;
R1-amino-3 -(3,5 -dimethylphenoxy)propan-2-ol; RS1-(dimethylamino)-3-(2-phenethylphenoxy)propan-2-ol; Sl-(dimethylamino)-3 -(2-phenethylphenoxy)propan-2-ol ; R1-(dimethyl amino)-3- (2-phenethyl phenoxy) propan-2-ol; RS1-(benzylamino)-3-(3-(trifluoromethyl) phenoxy) propan-2-ol; Sl-(benzylamino)-3-(3- (trifluoromethyl) phenoxy) propan-2-ol; R1-(benzylamino)-3 -(3 -(trifluoromethyl)phenoxy)propan-2-ol; RS1- amino-3 -phenoxypropan-2-ol ; Sl-amino-3-phenoxy propan-2-ol; R1- amino-3 -phenoxypropan-2-ol; RS1-((3-chloro-2- methylphenyl) amino)-3-phenoxy propan-2-ol; S1-((3-chloro-2-methylphenyl)amino) -3 -phenoxypropan-2-ol; R1-((3 -chloro-2-methylphenyl) amino)-3-phenoxypropan-2-ol; RS1-((2-((2,4-dichloro phenyl)amino) ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2,4-dichlorophenyl) amino) ethyl)amino)-3-phenoxypropan-2-ol;
R1-((2-((2,4-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol;
RS1-((3-(aminomethyl)phenyl)(methyl)amino)-3-phenoxypropan-2-ol; Sl- ((3-(aminomethyl) phenyl) (methyl)amino)-3-phenoxypropan-2-ol; R1-((3 -(aminomethyl)phenyl) (methyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol;
S1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2,6-dichloro phenyl) amino) ethyl)amino)-3-phenoxypropan-2-ol;
RS1-((2-((4-nitrophenyl)amino) ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((4-nitrophenyl)amino)ethyl) amino) -3-phenoxy propan-2-ol; R1-((2-((4-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((3-methoxy propyl) amino)-3-phenoxybutan-2-ol; S1-((3 -methoxypropyl)amino)-3 -phenoxybutan-2-ol; R1-((3 -methoxypropyl) amino)-3-phenoxybutan-2-ol; RS1-(isopropylamino)-3 -((2-methyl-1H-indo1-4-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((2-methy1-1H-indo1-4-yeoxy)propan-2-ol; R1-(isopropylamino)-3-((2-methy1-1H-indo1-4-yeoxy)propan-2-ol; RS 1-(isopropylamino)-3-((6-methylfuro l3 ,2-clpyridin-4-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methylfuro 113,2-clpyridin-4-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-methylfuro 113,2-clpyridin-4-yl)oxy) propan -2-ol; RS1-(isopropylamino)-3-(naphthalen-l-ylmethoxy)propan-2-ol; S1-(isopropyl amino)-3-(naphthalen-l-ylmethoxy) propan-2-ol;
R1-(isopropylamino)-3-(naphthalen-l-ylmethoxy) propan-2-ol; RS1-(isopropylamino)-3-((3-(4-methylpiperazin-l-y1) pyrazin -2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((3-(4-methylpiperazin-l-yl)pyrazin-2-yl)oxy) propan-2-ol; R1- (isopropylamino) -3 -((3 -(4-methylpiperazin -1-yl)pyrazin-2-yl)oxy) propan -2-01; RS1-(2-nitro-1H-imidazol-1-y1)-3-phenoxypropan-2-ol; S1-(2-nitro-1H-imidazol-1-y1)-3-phenoxypropan-2-ol; R1-(2-nitro-1H-imidazol-1-y1)-3-phenoxypropan-2-ol; RS1-(6-amino-2-ethoxy-9H-purin-9-y1)-3-phenoxypropan-2-ol; S1-(6-amino-2-ethoxy- 9H-purin-9-y1)-3-phenoxy propan-2-ol; R1-(6-amino-2-ethoxy-9H-purin-9-y1)-3-phenoxypropan-2-ol; RS1-(isopropylamino )-3-((2-methylfurol3,2-clpyridin-4-yeoxy)propan-2-ol; S1-(isopropylamino)-3-((2-methylfuro 113,2-clpyridin-4-yl)oxy)propan-2-ol;
R1-(isopropylamino)-3-((2-methylfurol3,2-clpyridin-4-yl)oxy) propan-2-ol; RS1-(isopropylamino)-3-(p-tolyloxy)propan-2-ol; S1-(isopropylamino)-3-(p-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(p-tolyloxy)propan-2-ol; RS1-(isopropylamino)-34(5-methy1-3-morpholinopyrazin-2-yl)oxy)propan-2-ol; S1-(isopropy lamino) -3-((5-methy1-3-morpholinopyrazin-2-yl)oxy) propan-2-ol; R1-(isopropylamino) -3-((5-methy1-3-morpholinopyrazin-2-yl)oxy)propan-2-ol; RS1-(4-(2-chlorophenyl) piperazin-l-y1)-3-phenoxy propan-2-ol; S1-(4-(2-chlorophenyl) piperazin-l-y1)-3-phenoxypropan-2-ol; R1-(4-(2-chloro phenyl) piperazin-l-y1)-3-phenoxypropan-2-ol; RS1-(isopropylamino)-3-((2-methylthieno 113,2-clpyridin-4-yl)oxy)propan-2-ol; S1-(isopropyl amino)-3-((2-methylthienol3,2-clpyridin-4-yl)oxy) propan-2-ol; R1-(isopropylamino)-34(2-methylthienol3,2-clpyridin-4-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-ol;
S1-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-ol; R1-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-ol; RS1-((3,4-dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol;
S14(3,4-dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol; R1-((3 ,4-dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol;
RS1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol ;
R1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-phenoxypropan-2-ol; S1-(isopropylamino)-3-phenoxypropan-2-ol; R1-(isopropylamino)-3-phenoxypropan-2-ol;
RS1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol ;
RS1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; S 1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; R52-(isopropylamino)-1-(4-methoxyphenoxy)ethan-l-ol; S2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-l-ol ;
R2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-l-ol; RS(Z)-1-(isopropylamino) -3-(2-methoxy-4- (prop-1-en-1-y1) phenoxy) propan-2-ol; S(Z)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy) propan-2-ol; R(Z)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy) propan -2-01;
RS1-(isopropylamino)-3-(4-(2-(methylthio)ethoxy)phenoxy)propan-2-ol; S 1-(isopropylamino)-3-(4-(2-(methylthio)ethoxy)phenoxy)propan-2-ol;
R1-(isopropylamino)-3-(4-(2-(methylthio) ethoxy) phenoxy)propan-2-ol;
RS (E)-1-(isopropylamino)-3 -(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol;
S(E)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy)p ropan-2-ol;
R(E)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy)propan-2-ol;
RS1-(isopropylamino)-3-(mesityloxy)propan-2-ol; S1-(isopropylamino)-3 -(mesityloxy)propan-2-ol; R1-(isopropylamino)-3-(mesityloxy)propan-2-ol; RS1-(isopropylamino)-3-(4-((1-(methyl thio)propan-2-yl)oxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(4-((1-(methylthio)propan-2-yl)oxy) phenoxy) propan-2-ol; R1-(isopropylamino)-3-(4-((1-(methylthio)propan-2-yl)oxy) phenoxy) propan-2-ol; RS1-(isopropylamino)-3-(4-(3-methy1-1H-indo1-2-yephenoxy)propan-2-ol; S1-(isopropylamino)-3-(4-(3-methy1-1H-indo1-2-y1)phenoxy)propan-2-ol; R1-(isopropyl amino )-3-(4-(3-methy1-1H-indo1-2-y1)phenoxy)propan-2-ol; RS1-(isopropylamino)-3-(2-((5 -methylisoxazol-3 -yl)methoxy)phenoxy)propan-2-ol;
S1-(isopropylamino)-3-(2-((5-methyl isoxazol -3-y1) methoxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(2-((5-methyl isoxazol -3 -yl)methoxy)phenoxy)propan-2-ol ; RS1-(isopropylamino)-3-(2-((3-methylisoxazol-5-yl)methoxy) phenoxy)propan-2-ol;
S1-(isopropylamino)-3 -(2-((3 -methylisoxazol-5 -yl)methoxy)phenoxy) propan-2-ol; R1-(isopropylamino)-3-(2-((3 -methylisoxazol-5 -yl)methoxy)phenoxy)propan-2-ol;
RS1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
S1-(4-((2H-1,2,3 -triazol-2-yl)methoxy)phenoxy)-3 -(isopropylamino)propan-2-ol; R1-(4-((2H-1,2,3 -triazol-2-yl)methoxy)phenoxy)-3 -(isopropylamino)propan-2-ol;
RS1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
S1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy) propan-2-ol; R1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy) propan-2-ol; RS
i-(4-(2-(2H-1,2,3 -triazol-2-yl)ethoxy)phenoxy)-3 -(isopropylamino)propan-2-ol; S1-(4-(2-(2H-1,2,3 -triazol-2-yl)ethoxy)phenoxy)-3 -(isopropylamino)propan-2-ol; R1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy) phenoxy) -3 -(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(3-methoxyphenoxy) propan -2-01; S1-(isopropylamino)-3 -(3 -methoxyphenoxy)propan-2-ol;
R1-(isopropylamino)-3 -(3 -methoxy phenoxy)propan-2-ol; RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino) propan-2-ol; S1-(4-(2-(1H-1,2,4-triazol-1-y1) ethyl)phenoxy)-3-(isopropylamino) propan-2-ol; R1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropyl amino) propan-2-ol; RS1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino) propan -2-ol; S1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl) phenoxy)-3-(isopropylamino)propan-2-ol;
S1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl) phenoxy) -3-(isopropylamino)propan-2-ol; R1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenoxy)-3-(isopropyl amino) propan-2-ol;
S1-(4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenoxy)-3-(isopropylamino) Z
io-z-ualaid(Rouatidamu-z-pCtpaul- SN
tio-z-ualaid(oulurepCdaidos-0-TN tio-z-ualaid(ouIumpCdaidosI)- s 10-z-ualaid(ouIumpCdaidosI)- -1.1Ip1.1/Cclou1-ut1-z))- jsN t10-z-uudaid(oulumpCdaidosI) - -(iCxotiatid(pCtpa(pC-j -IozatCd-H j )-6-0- IN tIo-z-uudaid(ouIumpCdaidosI)- -(iCxouatid(pCtpa(pC
--IozaLcd-11 -1)-617)- I S tio-Z-uudaid(oul-urevcdaidosI)--(aouatid(F400/C-j lozatcd-HT )-6-17) 0 - jSN Io-z-uuinq(oItppqoi-d)-t-(ouIumpCdoJdosI)- TN tio-z-treinci(oNipqm-d)--17-(ouIum pCdaidosI) - I S
tio-z-treinci(amipqm-d)--17-(ouIumpCdaidosI)- sN tIo-z-ualaid(Rouatidamu- --pCtpaul -c)- -(ollItztupCdai-dos!)- jN tIo-z-uudaKI(Rouatidamu-NiCtpaul-z)- -(oulutupCdai-dosI)-T s Io-z-uudaKI(Rouatidamu-NiCtpaul-z)- -(oulutupCdai-dosI)- sN tio-z-uudaikao(pC-oullogthotu-9))- -(ouItu-epCdaTdosI)- jN tIo-z-uudaikao(pC- -1.171pl.i/CdouI1otichoul-9)) gz - -(oul-urepCdaidos!)- js tIo-z-uudaikao(pC- -1.171pl.i/Cdoullotichoul-9))--(ollItztupCdai-dos!)- T sN
tio-z-uudaKI(Ropqm-u1)- -(ollItztupCdai-dos!)- jN tIo-z-uudaKI(Ro1iqm-u1)- -(ollItztupCdai-dosI) - I S tio-z-uudaKI(Ropqm-u1)- -(ouItu-epCdaidos!)- sN tio-z-ualaidpCuatid- -(ollItztupCdai-dosI) -IN tio-z-uudaidpCuatid- -(ollItztupCdai-dos!)- js tio-z-uudaidpCuatid- -(ollItztupCdai-dosI) - I SN
tptreclaid (I/Cuagdiampatu- _(,c-xodojd(ouItnui,cdojdosI)- N puudaKI OZ
(pCuatidiampaul- -(iCxodai-d(ouIumpCdaidosI)-tpuudaid(pCuatidiampaul - -(iCxodo.KI(oul-umpCdaidosI)- sN
tio-z-ualaid(Ro(pC-z-uIzatCd(amipCuatid) - -(ollItztupCdai-dos!)- TN tio-z-uudaikao(pC-z-uIzatCd(oNipCuatid)-0)- -(ollItztupCdai-dosI) - I S tio-z-uudaikao(pC-z-uIzatCd(oNipCuatid)-0)- -(oul-ulupCdaidosI)- sN
tp-z-ualaid(RopC
-z-uatutptid-eu)- -(ollItztupCdai-dos!)--iN
tio-z-uudaKI(RopC-z-uaimptideu)- g - I S tio-z-uudaKI(RopC-z-uaimptid-eu)- -(ollItztupCdai-dos!)- sN tp-z-ualaid(Ro(pc--fr -umItuy/Cd(o-mipCtpaul)-))- -(ollItztupCdai-dos!)- TN tio-z-ualaikao(pC-t-uml-uuy/Cd(oNipCtpaul) - -(ollItztupCdai-dos!)- s tio-z-uudaikao(pC-t-umItuy/Cd(amipCtpaul)-6)-- I SN t10-z-uudaid(Ro(pC- I -u Iulilliduu-PCIllm-u-17))- -(ouItaupCdaidosI)- TN tp-z-ualaid(iao(PC
- -uaimpticteupCtpaul-t))- -(olquu-epCdaidosI)- s tp-z-tredaKI(Ro(pC- -uompticteupCtpaul 0 I
- -(ollItztupCdai-dos!)-T sN
tomumuoIdaid(pCuatikaodaid(ouIumpCdaidosI)-tomumuoIdaid(pCuatikaodaid(ouIumpCdaidosI)- -/C3co.ipiCti-z)--17)-Ns tomumuoIdaid (pCuatid(Rodaid (mmu-epCckudosI) - -/C3co.ipiCti-z)--17)-NsN tio-z-uudaKI (mmu-epCckudosI) - -(/C3coliatid(Rotpa (pc-z-ioz-eyi-CV T -Hz)-z)-t)-TN
tio-z-uudaKI (mmu-epCckudosI) - -(iCxotiatid(Rotpa (pc-z-ioz-eyi-CV s t10-z-uudaid(ouTrepCdaidosI)-(Rouatid (ampa(pC-z-ioz-eyi-CV -Hz)-z)-t)-T sN tp-z-ualaid(oupirepCdaidosI)- -(iCxouatid(Rotpaul(pC
z` -1_0)-0 -TN t10-z-uudaid(oulumpCdaidosI)- -(iCxouatid(Rotpaul(pC-z-ioz-eyi-CV
-HZ))--17)- I S tio-z-ualaid(oupirepCdaidosI)- -(iCxouatid(Rotpaul(pC-z-ioz-eyi-CV sN
10-z-ualaid(oupirepCdaidosI)- -(iCxouatid(Cxotpa(pC- T 10z-elm17' z` TN
tIo-z -uudaKI
8L600/810ZSI1IIDd EILtOZ/8I0Z OM
S1-(tert-butylamino)-3 -(3 -methyl-2-nitrophenoxy)propan-2-ol;
R1-(tert-butylamino)-3 -(3-methy1-2-nitrophenoxy)propan-2-ol; RS1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol S1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol;
R1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino) propan-2-ol; S1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino) propan-2-ol; R1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3 -(isopropylamino) propan-2-ol ;RS1-(3- amino phenoxy) -3 -(2-methyl-1H-benzo [di imidazol-1-yl)propan-2-ol;
S1-(3 -aminophenoxy)-3 -(2-methy1-1H-benzo [di imidazol-1-yl)propan-2-ol;R1-(3 -aminophenoxy)-3 -(2-methyl-1H-benzo lidll midazol-1-yl)propan-2-ol;RS1-(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3(isopropyl amino) propan-2-ol;S1-(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3-(isopropylamino) propan-2-ol; R1-(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3-(isopropyl amino)propan-2-ol; RS1-((2-((6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxy propan -2-01; S1-((2-((6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxypropan-2-ol; RS1-(4-(2-(cyclo propyl methoxy)ethyl)phenoxy)-3 -(isopropylamino)propan-2-ol; S1-(4-(2-(cyclopropyl methoxy) ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(cyclopropylmethoxy) ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R53 ,3'-(butylazanediyebis (1-phenoxypropan-2-ol); S3,3'-(butylazanediyebis(1-phenoxypropan-2-ol);
R3 ,3'-(butylazanediy1)bis (1-phenoxypropan-2-ol);
RS1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-(isopropylamino)propan-2-ol;S1-(44(2-iso propoxyethoxy) methyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(44(2-isopropoxyethoxy) methyl) phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(3,4-dimethylphenoxy) - 3-(2,2,5 ,5 -tetra methyl-2,5-dihydro-1H-pyrrol-1-y1)propan-2-ol; S1-(3,4-dimethyl phenoxy)- 3 -(2,2,5,5 -tetra methyl-2,5-dihydro-1H-pyrrol-1-y1)propan-2-ol; R1-(3,4-dimethyl phenoxy)- 3-(2,2,5 ,5 -tetra methyl -2,5 -dihydro-1H-pyrrol-1-yl)propan-2-ol; R53-((2-hydroxy- 3 -phenoxypropyl) amino) propan-l-ol; S3 -((2-hydroxy-3 -phenoxypropyl)amino)propan-l-ol; R3 -((2-hydroxy-3 -phenoxypropyl)amino)propan-l-ol; RS5-(2-hydroxy-3-(isopropylamino)propoxy)chroman-3-y1 nitrate; S5 -(2-hydroxy-3 -(isopropylamino)propoxy)chroman-3 -yl nitrate; R5-(2-hydroxy-3-(isopropylamino)propoxy)chroman-3-y1 nitrate; RS1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-2-ol;
S1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3 -((6-methylpyrazin-2-yl)oxy)propan-2-ol;
S1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol;
R1-(isopropylamino)-3 -46-methylpyrazin-2-yl)oxy)propan-2-ol;
RSN-(8-(2-hydroxy-3-(isopropylamino)propoxy)-1,2,3,4,4a,7,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)methanesulfonamide;
SN-(8-(2-hydroxy-3-(isopropylamino)propoxy)-1,2,3,4,4a,7,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)methane sulfonamide;
RN-(8-(2-hydroxy-3 -(isopropylamino)propoxy)-1,2,3 ,4,4a,7 ,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)methanesulfonamide; RS1-(isopropylamino)-3-((6-methoxy pyridazin-3-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methoxypyridazin-3-yl)oxy)propan-2-ol; R1-(isopropylamino)-3 -((6-methoxypyridazin-3 -yl)oxy)propan-2-ol;
RS1- (isopropylamino)-3-(thiazol-2-yloxy)propan-2-ol; S1-(isopropylamino)-3 -(thiazol-2-yloxy) propan -2-ol; R1-(isopropylamino)-3 -(thiazol-2-yloxy)propan-2-ol;
RS1-(isopropylamino)-3-(4-nitrophenyl) propan-2-ol; S1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; R1-(isopropylamino)-3 -(4-nitrophenyl)propan-2-ol ; RS1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; .. Sl-(isopropylamino)-3 -(4-nitrophenyl)propan-2-ol; R1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; RS1-(4-ally1-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-ally1-2-methoxy phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-ally1-2-methoxyphenoxy)-3-(isopropyl amino) propan-2-ol; RS1-(isopropylamino)-3-(2,4,5-trimethylphenoxy)propan-2-ol; S1-(isopropylamino) -3 -(2,4,5-trimethylphenoxy)propan-2-ol ;
R1-(isopropylamino)-3-(2,4,5-trimethylphenoxy) propan-2-ol; RS1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol; R1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol; RS1-(4-(2-methoxyethyl)phenoxy)-3 -((3 -phenylpropyl)amino)propan-2-ol;
S1-(4-(2-methoxyethyl) phenoxy)-3-((3-phenylpropyl)amino)propan-2-ol; R1-(4-(2-methoxyethyl) phenoxy)-3-((3-phenylpropyl)amino)propan-2-ol; RS1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin -1-y1) propan-2-ol; S1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-l-yl)propan-2-ol R1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-l-yl)propan-2-ol;
R53,3'-((2-hydroxyethyl)azanediy1)bis (1-phenoxypropan-2-ol) ; S3,3'-((2-hydroxyethyl) azanediyl) bis (1-phenoxy propan-2-ol); R3 ,3'((2-hydroxyethyl)azanediy1)bis (1-phenoxypropan-2-ol) ; RS1-(2-(methylthio)phenoxy)-3-(2,2,6,6-tetramethylpiperidin-l-yl)propan-2-ol;
S1-(2-(methylthio) phenoxy) -3-(2,2,6,6-tetramethylpiperidin-l-yl)propan-2-ol; R1-(2-(methylthio)phenoxy) -3-(2,2,6,6- tetramethyl piperidin-l-yl)propan-2-ol; RS1-(3,6-dihydropyridin-1(2H)-y1)-3-(o-tolyloxy)propan-2-ol; S1-(3,6-dihydropyridin-1(2H)-y1)-3-(o-tolyloxy)propan-2-ol; R1-(3,6-dihydropyridin-1(2H)-y1)-3-(o-tolyloxy)propan-2-ol; RS1-((4-methoxyphenyl)amino)-3-phenoxy propan-2-ol; S1-((4-methoxyphenyl)amino)-3-phenoxypropan-2-ol; R1-((4-methoxyphenyl) amino)-3-phenoxypropan-2-ol;
RS1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; S 1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3 -(m-tolyloxy)propan-2-ol; R1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS i-(4-(2-methoxyphenyl)piperazin-l-y1)-34m-tolyloxy)propan-2-ol; S14442-methoxyphenyl)piperazin-l-y1)-34m-tolyloxy)propan-2-ol;
R1-(4-(2-methoxyphenyl)piperazin-l-y1)-34m-tolyloxy) propan-2-ol; RS1-((2-((2,5-dimethylphenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; Sl-((2-((2,5-dimethylphenyl)amino)ethyl)amino)-3 -(m-tolyloxy)propan-2-ol ; R1-((2-((2,5-dimethyl phenyl)amino) ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS1-(((l-benzy1-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol;
S1-(((l-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol;
R14((l-benzy1-3,5-dimethy1-1H-pyrazol- 4-yl)methyl) (methyl)amino)-3-phenoxypropan-2-ol; RS1-(tert-butylamino)-3 -((3-methyl- 1H-indol- 4-yl)oxy)propan-2-ol;
S1-(tert-butylamino)-3-((3 -methy1-1H-indo1-4-yl)oxy)propan-2-ol; R1-(tert-butylamino)-34(3-methy1-1H-indo1-4-y1)oxy)propan-2-ol; RS1-(methyl amino) -3-phenoxypropan-2-ol; Sl4methylamino)-3-phenoxypropan-2-ol; R1-(methyl amino) -3 -phenoxypropan-2-ol; RS1-((2-hydroxyethyl)amino)-3-phenoxypropan-2-ol; S1-((2-hydroxyethyl)amino)-3-phenoxypropan-2-ol; R14(2-hydroxyethyl)amino)-3-phenoxypropan-2-ol; RS14(4-methylthiazol-5-yl)oxy)-34442-(neopentyloxy)phenyl)piperazin-l-y1)propan-2-ol;
S14(4-methylthiazol-5-yl)oxy)-34442-(neopentyloxy)phenyl)piperazin-l-y1)propan-2-ol; R1-((4-methylthiazol-5-yeoxy)-34442-(neopentyloxy)phenyl)piperazin-l-y1)propan-2-ol; RS1-(4-(2-ethoxyphenyl)piperazin-l-y1)-34(4-methylthiazol-5-yl)oxy)propan-2-ol; S1-(4-(2-ethoxy phenyl) piperazin-l-y1)-34(4-methylthiazol-5-yl)oxy)propan-2-ol; R14442-ethoxyphenyl) piperazin-l-y1)-34(4-methylthiazol-5-yl)oxy)propan-2-ol; RS1-phenoxy-3 -(quinuclidin-3-ylamino)propan-2-ol; Sl-phenoxy-3-(quinuclidin-3-ylamino)propan-2-ol; Rl-phenoxy-3-(quinuclidin-3-ylamino)propan-2-ol; RS1-(4-(3-chlorophenyl)piperazin-l-y1)-34(4-methylthiazol -5 -yl)oxy)propan-2-ol; S1-(4-(3-chlorophenyl)piperazin-l-y1)-34(4-methylthiazol-5-yl)oxy) propan -2-01; R14443-chlorophenyl)piperazin-l-y1)-34(4-methylthiazol-5-yeoxy)propan-2-ol;
RS14((6,7-dimethoxyisochroman-l-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol;
S1-(((6,7-dimethoxyisochroman-l-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; R14((6,7-dimethoxy isochroman-l-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; RS1-((2-aminoethyl)amino)-3-phenoxy propan-2-ol; S1-((2-aminoethyl)amino)-3-phenoxypropan-2-ol; R1-((2-aminoethyl)amino)-3-phenoxypropan-2-ol;
RS1-(4-(2-(isopentyloxy)phenyl)piperazin-l-y1)-3-((4-methylthiazol-5-yeoxy)propan-2-ol;
S1-(4-(2-(isopentyloxy)phenyl)piperazin-l-y1)-34(4-methyl thiazol-5 -yl)oxy)propan-2-ol; R14442-(isopentyloxy)phenyl)piperazin-l-y1)-34(4-methyl thiazol-5 -yl)oxy)propan-2-ol; RS1-(4-(2-isobutoxyphenyl)piperazin-l-y1)-34(4-methyl thiazol-5-yl)oxy)propan-2-ol; S1-(4-(2-isobutoxyphenyl)piperazin-l-y1)-34(4-methylthiazol-5-yl)oxy) propan-2-ol; R1-(4-(2-isobutoxyphenyl)piperazin-l-y1)-34(4-methylthiazol-5-yl)oxy) propan-2-ol; RS1-((2-((2,6-dimethylphenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2,6-dimethyl phenyl)amino)ethyllamino)-3-phenoxypropan-2-ol; R1-42-42,6-dimethylphenyl) aminolethyllamino)-3-phenoxypropan-2-ol;
RS1-((2-((2-chlorophenyl)amino)ethyllamino)-3-phenoxypropan-2-ol; S14(2-42-chlorophenyllaminolethyllamino)-3-phenoxypropan-2-ol; R1-((2-42-chlorophenyllaminolethyeamino)-3 -phenoxypropan-2-ol ;
RS1-phenoxy-3 -((2-(o-tolylamino)ethyl)amino)propan-2-ol; Sl-phenoxy-3-((2-(o-tolylamino)ethyl)amino)propan-2-ol Rl-phenoxy-3-((2-(o-tolylamino)ethyl)amino)propan-2-ol;
RS1-((4-methoxybutyl)amino)-3 -phenoxypropan-2-ol; S1-((4-methoxybutyl)amino)-3-phenoxypropan-2-ol;
methoxybutyllamino)-3-phenoxypropan-2-ol;
RS1-((2-((3-nitrophenyl)amino)ethyllamino)-3-(m-tolyloxy)propan-2-ol; S1-((2-((3-nitrophenyl)amino)ethyllamino)-3-(m-tolyloxy)propan-2-ol R14(2-43 -nitrophenyllaminolethyllamino)-3-(m-tolyloxy)propan-2-ol; RS1-((2-((3-nitrophenyl) amino) ethyllamino)-3-(m-tolyloxy)propan-2-ol; S1-((2-((3-nitrophenyl)amino)ethyllamino)-3-(m-tolyloxy)propan-2-ol; R1-((2-((3-nitrophenyl)amino)ethyllamino)-3-(m-tolyloxy)propan-2-ol;
RS1-((2-((2-nitrophenyl)amino)ethyllamino)-3-phenoxypropan-2-ol;
S14(2-((2-nitrophenyl) amino) ethyllamino)-3-phenoxypropan-2-ol;
R1-42-42-nitrophenyllaminolethyllamino)-3 -phenoxypropan-2-ol; RS1-((2-((2-nitrophenyl)amino)ethyllamino)-3-phenoxypropan-2-ol; S1-((2-((2-nitrophenyl)amino)ethyllamino)-3-phenoxypropan-2-ol; R1-((2-((2-nitrophenyl)amino) ethyllamino)-3-phenoxypropan-2-ol;RS1-(isopropylamino)-3-((l-tosy1-1H-indo1-4-yl)oxy) propan -2-01;
S1-(isopropylamino)-3-41-tosy1-1H-indo1-4-ylloxylpropan-2-ol; R1-(isopropylamino) -3-((l-tosy1-1H-indo1-4-yl)oxy)propan-2-ol.
N-methyl-N-(trifluiwomethy1)-2-41,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-yDoxy) ethan-1-amine, N,N-bis(trifi iioroniethyl)-241,7,7 -tri n iethy1-2-ph enyibicyclo [2.2.1]heptan-2-yl)oxy)ethan-i-amine, 24(1,7-dime thy1-2-pheny1-7-(trifluoromethyl)bicyclo [2.2.1 iheptan-2-yl)oxy)-N,N-bis Orifi uoromethypethan- 1-amine, 2-(( I-methyl -2-pheny1-7,7-bis(trifi uoromethyDbicyclo[2.2.11hept an-2-ypox bis (trifluoromethyl)ethan-1-amine, N-inethy1-2-41-methy1-2-ptienyl-7,7-bis(trifiuoromethyDbicyc1o[2.2.1]heptan-2-yDoxy)-N-(trilluorometbyl)ethan-1-amine, N,N-dimethy1-2-41-mediy1-2-plieny1-7,7-bis(trifi uoromethyl)bicyclo [2.2.1]heptan-2-yl)oxy)ethan- 1- amine, 2-41,7-dimethy1-2-pheny1-7-(trifluoromethyl)bicyclo [2.2 1]heptan-2-y1)oxy)-N,N-ditnethylethan-1 -amine, and N,N-dimethy1-24(1,7,7-trimethyl-2-(4-(trifluoromethoxy)phenyl)bic yclo[2.2. 1 lheptan-2-yl)oxy)ethan - 1 -amine.
2-phenyl-2-(3 ' -dimethylaminopropoxy)- 1,7 ,7 -trimethylbicyclo [2 ,2 ,11heptane ;
2-phenyl-2-(3 ' -diethylaminopropoxy)- 1,7 ,7-trimethylbicyclo [2 ,2,11heptane ;
2-(p-methoxy-phenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo(2,2,1) heptane; 2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo112,2,11heptane;
2-benzy1-2-(3'-dimethylamino-2'-methylpropoxy)-1,7,7-trimethyl-bicyclo[2,2,11 heptane;
2-benzy1-2- (2-diisopropylaminoethoxy)- 1,7 ,7 -trimethyl-bicyclo [2 ,2,11heptane ;
2-benzy1-2-1'-(4'-benzylpiperaziny1)-propoxy1,7,7-trimethylbicyclo112,2,11 heptane;
2-benzy1-2- (3' -diis opropylaminopropoxy)- 1,7 ,7-trimethylbicyclo [2 ,2,11heptane ;
2-benzy1-2- (3' -diethylaminopropoxy)-1,7,7-trimethylbicyclo 112,2,11heptane;
2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo112,2,11heptane;
2-benzy1-2-(2'-diethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-(3'-dimethylamino propoxy) -1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-dimethylaminopropoxy)-2-(4'-methoxypheny1)-1,7,7-trimethylbicyclo[2,2,11 heptane;
2-(p-chloro-benzy1)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(p-chloro-benzy1)-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-dimethylamino-2'-methyl)-propoxy-2-(p-chloro-phenyl)- 1 ,7,7-trimethylbicyclo [2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,11heptane;
2-(2'-dimethylaminoethoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,11heptane;
2-(3-diethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,11heptane;
2-(2'-diethylaminoethoxy)-2-(2'-thieny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-dimethylaminopropoxy)-2-(2'-thieny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-diethylaminopropoxy)-2-(2'-thieny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-3'-(N-cyclohexyl-N-methyl)aminopropoxyl-1,7,7-trimethylbicyclo[2,2,11 heptane;
2-(p-methoxypheny1)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,11 heptane;
(1 R,2 S ,4R)-(-)-2- [(2'- { N,N-dimethylamino } -ethoxy)] -2 - [phenyl] - 1,7 ,7 -trimethylbicyclo [2,2, 1 lheptane ;
(1R,2S,4R)-(-)-2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,11 heptane;
(1R,2S,4R)-(-)-2-benzy1-2-(2'-methy1-3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo [2,2,1] heptane;
(1RS,2RS,4RS)-2-pheny1-2-(2'-dimethylaminoethoxy)-1,7,7 trimethylbicyclo[2,2,11 heptane;
(1S,2R,4S)-(+)-2-pheny1-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,11 heptane;
N,N-dimethy1-2-[[(1R,3S,4R)-4,7,7-tri ethy1-3-phenyl-3-bicyclo[2.2.11 heptanyli oxy]
ethanamine (deramciclane); N-methyl-N-(trifluoromethyl)-24(1,7,7-trimethyl-2-plienylbicyclo [2.2.1]heptan-2-y1)oxy) ethan-l-amine, N,N-bis(trifluoromethyl)-2-41,7,7-trimethyl-2-phenyibicyclo[2.2.11heptan-2-yi)oxy)ethan-1-amine, 2-41,7-dimethyl-2-phenyl-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-y1)oxy)-N,N-bis(iifluoromethyl)eth an-1-a mine, 24(1-methyl-2-plienyl-7,7-bis(trifluoromethyl)bicyclo[2.2.11heptan-2-y1)oxy)-N,N-bis(trifluoromethyl)ethan-1-amine, N-methy1-2-41.-methyl-2-phenyl -7,7-hi s(trifl uororriethyl)bicyc1o[2.2.11heptan-2-ypoxy)-N-(trifluoromethyl)ethan-1-amine, N,N-dimethy1-2-41-methy1-2-pheny1-7,7-bis(trifluoromethyl)bicyclo[2.2.11hentan-yl)oxy)ethan- 1-amine, 2-01,7-dimethy1-2-pheny1-7-(irifluoromethy1)bicyc1o[2.2.1]heptan-2-y1)oxy)-N,N-dimethylethan-1--amine, and N,N-dimethy1-24(1,7,7-trimethy1-244-(trifluommethoxy)phenyl)bicyclo[2.2.1]heptan-2-y1)oxy)eth an- 1-amine.
2-pheny1-2-(2-dimethylaminoethoxy)-1,7,7-trimethylbicyclo 112,2,11heptane;
2-phenyl-2-(3'-dimethylaminopropoxy)- 1,7 ,7-trimethylbicyclo[2,2,11heptane;
2-phenyl-2-(3'-diethylaminopropoxy)- 1,7 ,7-trimethylbicyclo[2,2,11heptane;
2-(p-methoxy-phenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-(3'-dimethylaminopropoxy)- 1,7 ,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-(3'-dimethylamino-2'-methylpropoxy)-1,7,7-trimethyl-bicyclo[2,2,11 heptane;
2-benzy1-2-(2-diisopropylaminoethoxy)- 1,7 ,7-trimethyl-bicyclo[2,2,11heptane;
2-benzy1-2-1'-(4'-benzylpiperaziny1)-propoxy1,7,7-trimethylbicyclo112,2,11 heptane;
2-benzy1-2-(3'-diis opropylaminopropoxy)- 1,7 ,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo [2,2,11heptane;
2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2,2,11heptane;
2-benzy1-2-(2'-diethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-(3'-dimethylaminopropoxy)- 1,7 ,7-trimethylbicyclo[2,2,11heptane;
2-(3'-dimethylaminopropoxy)-2-(4'-methoxypheny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(p-chloro-benzy1)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(p-chloro-benzy1)-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-dimethylamino-2'-methy1)-propoxy-2-(p-chloro-pheny1)-1,7,7-trimethylbicyclo112,2,11 heptane;
2-(3'-dimethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,11heptane;
2-(2'-dimethylaminoethoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,11heptane;
2-(3-diethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,11heptane;
2-(2'-diethylaminoethoxy)-2-(2'-thieny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-dimethylaminopropoxy)-2-(2'-thieny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-(3'-diethylaminopropoxy)-2-(2'-thieny1)-1,7,7-trimethylbicyclo[2,2,11heptane;
2-benzy1-2-3'-(N-cyclohexyl-N-methyl)aminopropoxyl-1,7,7-trimethylbicyclo[2,2,11 heptane;
2- (p-methoxypheny1)-2-(3'-dimethylaminopropoxy)- 1,7,7- trimethylbicyclo 112,2,11 heptane;
(1R,2S,4R)-(-)-2- [(2'- { N,N-dimethylamino}-ethoxy)1-2- [phenyl] -1,7,7-trimethylbicyclo [2,2,11 heptane;
(1R,2S ,4R)- (-)-2 -benzy1-2-(3-dimethylaminopropoxy)- 1,7,7- trimethylbicyclo [2 ,2 ,11 heptane;
(1R,2S ,4R)- (-)-2 -benzy1-2- (2' -methyl-3' -dimethylaminopropoxy)- 1,7,7-trimethylbicyclo 112,2,11 heptane;
(1RS ,2RS ,4RS)-2 -pheny1-2 - (2'-dimethylaminoethoxy)- 1,7,7 trimethylbicyc lo [2,2 ,11 heptane;
(1S ,2R,4 S)-(+)-2-pheny1-2- (2'-dimethylaminoethoxy)- 1,7,7 -trimethylbicyclo [2,2 ,11heptane ; N,N-dime thyl -2- [ i( R,3 S AR)-4,7,7-trim ethyl-3 -pheny1-3-bicyclo [2.2.1 liteptanyljoxy]ethanannne (deramciclane); or an acid addition salt thereof.
(4bS ,8aS ,9 S)-11 -methyl-3 - (trifluoromethoxy)- 6,7 ,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene;
(4bS , 8 aS ,9S)-3 -(trifluoromethoxy)-11- (trifluoromethyl)-6,7 ,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene;
(4bS , 8aS,9 S)-3 -methoxy- 11 -(trifluoromethyl)- 6,7, 8 ,8 a,9,10-hexahydro-5H-9 ,4b-(epiminoethano)phenanthrene.
Another embodiment of the invention is a composition comprising an acid addition salt of deramciclane and an acid addition salt of dextromethorphan.
is trifluoromethyl derivative of Ml.
In some embodiments, the compounds of Formula I form addition salts of 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid, and 4-(nitrooxy)butanoic acid. In another embodiment, the acid addition salt is of 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid, and 4-(nitrooxy)butanoic acid.
OH
0 ThC)L .....x>1-y1 Aspartate Galactopyranosyl-D-0 NI-1 gluconic acid (Lactobionate) HO
Benzenesulfonate = ii(:' HO
0H0/, OH
(Besylate) -0 Malate "*Tr'sy.11..0 HO ./OH
Benzoate . Maleate 0-C)) -o Bicarbonate ..A. 0 0 OH 0 Mandelate 410' OH
Bitartrate HO...1(.1,y,OH 0 0 OH Mesylate Bromide Br 0 Methylbromide -Br 0 Camphor sulfonic acid !Aki-------s M
(Camsylate) 0 ethylnitrate .---o ."":*-0 Chloride Cl- it Methylsulfate -- -4.c20 c?
Citrate Galactaric Acid (Mucate) OH OH Ho.r.) OH
Decanoate Napsy Slate 1010 0 0 OH
OH
Edetate H0.1),Nr=LI W
N ____ OH 0 Nitrate HO.) - 7 Lauryl sulfate (Estolate) ..,...................õ......fl Oleate Pamoate (4,4'- 41 Ethanesulfonate (Esylate) ,..--..1 methylenebis(3- iipik -40) c., -0 0 0 hydroxy-2- 011111 Fumarate osri -..........11-0 o OH
naphthoate)) HO'X?L N 'LCD
Gluceptate H00..........k.ix.4.)4.0 0H
Pantothenate 0 OH H
3H OH 7H Phosphate Gluconate Hos....0i:.....1 22.:...vL.0 Hok "I c`1 . 10 7.. 0'., polygalacturonate .-,e'0 t.",0- A.1, ,OH
3H 31-1 HO , HO' , HO , Glutamate y 1 Propionate 0 ......:20 0 t.........x0 Salicylate Ce0.,c.), Glycolate HOõ......1": 0 Stearate )1-0 )DN 0 0 Glycollylarsanilate HO. A. Succinate H o0 Hexanoate ....................Z0 HO so Sulfate O-S-0 g Hexylresorcinol Tartrate 0.Tri;j01.0 N ...... ri ...0 Hydroxynaphthoate 0 OH
Teoclate (8-chloro-1,3-dimethy1-7H-purine-2,6-dione) Isethionate HO.--,3ssf Iodide I- Ci, "s?- OH
>--(Lactate Tosylate g
0, 0, A II ikr0, R,n(r- :_risi r 0,------.4õ I
,N
" I jri l'.1)11110111 1, 11(1> 11C il"I'l Formula 1-Acid-Formula 11 -Ho - ,
(see for example, Rautio et al., The expanding role of prodrugs in contemporary drug design and development, Nature Reviews Drug Discovery, published online at http://dx.doi.org/10.1038/nrd.2018.46 (27 April 2018); Stella, Prodrugs: Some thoughts and current issues. J. Pharm. Sci. 99,4755-4765 (2010); Clas et al., Chemistry-enabled drug delivery (prodrugs): recent progress and challenges. Drug Discov. Today 19, 79-87 (2014); Rautio et al., Prodrugs ¨ Recent approvals and a glimpse of the pipeline. Eur. J. Pharm. Sci.
109, 146-161 (2017); Rautio et al. Prodrugs: design and clinical applications. Nat. Rev.
Drug Discov. 7, 255-270 (2008);Stella et al., Prodrug strategies to overcome poor water solubility. Adv. Drug Deliv.
Rev.59, 677-694 (2007); Kumpulainen et al. Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol. Eur. J. Pharm. Sci. 34, 110-117 (2008); Hale et al. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J. Med. Chem. 43, 1234-1241 (2000); Ishikawa et al. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg. Med. Chem. 11, 2427-2437 (2003); Mehellou et al., Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. ChemMedChem 4, 1779-1791 (2009); Thornton et al., Nucleoside phosphate and phosphonate prodrug clinical candidates. J. Med.
Chem. 59, 10400-10410 (2016); Pradere et al., Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem. Rev.114, 9154-9218 (2014); Starrett et al. Synthesis and in vitro evaluation of a phosphonate prodrug: bi s(pi valoyloxy methyl) 9-(2-phosphonylmethoxyethyl) adenine. Antiviral Res.19, 267-273 (1992); Starrett et al. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 942-(phosphonomethoxy)ethyl] adeni ne (PMEA). J. Med. Chem. 37, 1857-1864 (1994);
McGuigan et al. Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T).
Antivir. Chem.
Chemother. 9, 473-479 (1998); McGuigan et al., Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency. Antivir. Chem. Chemother. 9, 109-115 (1998); Erion et al. Design, synthesis, and characterization of a series of cytochsome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver. J.
Am. Chem. Soc. 126, 5154-5163 (2004); Yuan et al., Evaluation of in vitro models for screening alkaline phosphatase-mediated bioconversion of phosphate ester prodrugs. Drug Metab.
Dispos. 37, 1443-1447 (2009); Heimbach et al., Absorption rate limit considerations for oral phosphate prodrugs. Pharm. Res. 20, 848-856 (2003); Kadow et al., Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxynaethyl prodrug of the HIV-1 attachment inhibitor 2-(4-benzo y I -I-pi perazin y1)-1. -(4,7-di methoxy- I H-pyrrolo[2,3-c]pyridin-3-y1)-2-oxo ethanone (BMS-488043). J. Med. Chem. 55, 2048-2056 (2012); Heimbach et al., Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int. J. Pharm.
261, 81-92 (2003);
all of which are incorporated herein by reference in their entirety).
P. R, R, IV 'N1-1.x). F, -(, H2)õ ......
Fr"' \ N -IC 1-I,), IC HA, RI' ..,,,, \
)---\ 0 =N¨(c0,). N
li, I
R,...".'c.......,\? 011 õ......c......,,..1,c, R4 ols 4o()-r))/2_, )----0\
/--o (7(1\ R4 ..\,:.;-' 0 I ,. 0 , ? 0-- \
..õ..0 k )....../} 0)......0 ( I \
\ 0 \
\ il ) 'N....KRA, RI- ."=(µ [2)õ ( , R, ).......\ \
/I ;I' R, 0,..t...4.....
R,.."...N N., ,,-;;,1 ........), .µ......
P-a n P-11 1 -NII
0 " P-9 R, R12 P-10 PA-1 PA-2 2¨
(õ -µ. -( III), Rj" (µ II,), crir \ Ck ,sr R./ ..."(I II,S, ') CI_ N CI CI
1.,).
4 ,'.11, r 0....s \
PF-1 PF-2 PF-3 PF-4 PE-5 PF-6 )-CI PF-7 PF-8 \ 0 \
0,õ 7' R' PT-1 PT-2 PT-3 PT-4 / s' --. PT-5 PT-6(3 -0 (---0;4 M r AO
'? r' i PT-11 R'..") 124 ..) c2 s, 4 )__/_ ;1,, .-(µ [2,,, l' r\ 0 ir, ) PT-14 , PT-15 PT-16 PT-17 PT-18 )-40 o PT-19 01'.
1õ-= NI(CH2C1,.,) A, r" \ I 12 A.
c R4i µ t: ..--ccA-n 4 h , PT-22 0# `/NI ...... ria R, PT-21 PT-23 PT-24(1\ s PT-25) \r4-, ....-'''s PT-26 R s2 2y("r(i) 71- \___ 4.- 4 4 k"
..Ø...c, r ¨0 0-,I) PT-27 PT-28 PT-29 PT-30 PT-31 PT-32 ) Fl T' R.CII,)n Rr 'ICH, \
R4 P PT-33 PT-34 =..,' / ' '\P = Phosphate PA = PhosphorAmidate PF = PhosphonoFluoridate PT=PhosphoroThioate
- ez--,,=-za , ,.
<..., : õ `04)1,0,/
"
: ,_..\_ =
0_,,, _.
Compound 901 Compound 902 Compound 903 Compound 904 Compound 905 Compound 906 Compound 907 cx7X3( , (LT -) , \
I =ssi_AD. i L
Compound 908 Compound 909 Compound 411 \--' Compound Compound 910 Compound 912 i I r , r , r L 1L.- '- i .,. 0/ -' \-0,,r ), \-0r -' \-,x' ,0 yxc.C:C'CI ,- r...( ¨0;1, 7 ''' ,No", , r ¨ s¨,s.0 n ,_/¨.0 ,,s,0 0 , )-- 0 , Lc---0-,µõ CC-Ø. - CC,0õ *
c c . - IJIJ 914 Compound 915 Compound 916 Compound 917 Compound 918 Compound 919 Compound 920 Compound 921 c- \ P7 \ Q-- e(Ca, -QT \-Ck-\_ - Q.- \-C:5- Q7-CH_ -*I 4 4 -Cr 7 c 0')J-c' (::1:rs 4 s-7:p., --Th , ':
. õ 10 2- ='()C7- ",-s-X..; , ') 1"--, s'> : p r i -0-r- :-,7:õCr set Li -a CI. 1.=, `.k !..' I \
s "L
Compound 922 Compound 923 Compound 924 Compound 925 Compound 926 Compound 927 Compound 928 Compound 929 Compound 930 sr--2;.-- r -1 '-r_.., `A.-.1µ s.-J. i c' =-=:c. 1, s--CY" a ,_, i Compound 931 Compound 932 Compound 933 Compound 934 Compound 935 Compound 936 Compound 937 Compound 938 Compound 939 C(ja ' eCja ' C(Jai ' CC'134 eCja C;Cja :'f 0 41 '' Cria 1 L.
) L (0r1,/- -/- L, r- -i\ i- -0-1, Y / '' 4 '1 Compound 940 Compound 941 Compound 942 Compound 943) Compound 944 Compound 945 Racemate, 4, and R Ranemate,S, and R Racemate, S, and R
Compounds 946-948 Compounds 949-951 Compounds 952-954 ,,,,_)/ /
/ /
,-, I
404 5 \ 4,1\\, ,,)-a 4_,,,,pr 4,,,,:ico 4- 0õ,c. 4,--;:, 0-\ )-- ',. õL( Racemate ,S, and R Racemate, 5, and R Racemate, 5, and R Racemate, 0, and R Racemate, 5, and R Racemate, 5, and R Racemate, 5, and R
Racemate, 5, andIR
Compounds 955-957 Compounds 958-960 Compounds 961-963 Compound 964-966 Compound 967-969 Compound 970-972 Compound 973-975 Compound 976-978
= PhosphonoFluoridate, and PT=PhosphoroThioate, are also acetylcholinesterase inhibitors due to the phosphate, phorphoramidate, phosphofuoridate, and phosphothioate moieties that confer such activity (McGleenon et al., Acetylcholinesterase inhibitors in Alzheimer's disease, Br J Clin Pharmacol, 48, 471-480 (1999); Acetylcholinesterase Inhibitors and Memantine, Acetylcholinesterase Inhibitors for the Treatment of Mild to Moderate Dementia, and Memantine for the Treatment of Moderate to Severe Dementia in Alzheimer's disease(AD) (June 2013), available at http://www.fifeadtc.scot.nhs.uk/media/8535/cholinesterase-inhibitors-and-memantine-scp.pdf;
incorporated by reference).
METHODS OF USE
Ã22,164; psychotic disorders: Ã16,717; mood disorders: Ã19,238; addiction: Ã11,719; anxiety disorders: Ã11,687.
Apart from psychosis, these five disorders ranked amongst those with the lowest direct medical expenditure per subject (<Ã3000) (Feinberg et al., The size, burden and cost of disorders of the brain in the UK, J Psychopharmacol. 27(9): 761-770 (2013 September);
Projections of the Cost of Cancer Care in the United States: 2010-2020, J Natl Cancer Inst. 103(2): 117-128 (2011 Jan 19) incorporated in entirety by reference). It was estimated that the total cost of bipolar disorder (BP), also known as manic-depressive illness, made more than a decade ago was as high as S 45 billion per year. Most of this cost is accounted for by indirect costs related to reduced functional capacity and lost work. Patients with BP have higher rates of utilization of healthcare resources compared with the general population and compared with patients with other types of psychiatric conditions.
Comorbidity contributes to the heavy burden that BP imposes on society. Brain diseases represent a considerable social and economic burden in Europe. With yearly costs of about 800 billion euros and an estimated 179 million people afflicted in 2010, brain diseases are an unquestionable emergency and a grand challenge for neuroscientists. The global cost of mental health conditions alone was estimated at USS 2.5 trillion in 2010, with a projected increase to over US S6 trillion in 2030. Glioblastoma multiform is the most common malignant primary brain tumor in adults, with an estimated incidence of 4.43 per 100,000 person-years in the United States and a median age at presentation of 64 years. Symptoms often include headaches; nausea and vomiting; and progressive memory, personality, or neurologic deficits. While Alzheimer and other dementias are projected to show a 66% increase from 2005 to 2030. In the United States, depression is the second highest source of disability among women, and antidepressant non-responders are among the heaviest users of health care resources. Despite the clear decrease in quality of life and decreased productivity associated with depression, it is often underdiagnosed and inadequately treated.
Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013; incorporated by reference in its entirety). The number of unintentional overdose deaths from prescription pain relievers has soared in the United States, more than quadrupled since 1999. There is also growing evidence to suggest a relationship between increased non-medical use of opioid analgesics and heroin abuse in the United States (Pradip et al., Associations of Nonmedical Pain Reliever Use and Initiation of Heroin Use in the US, Center for Behavioral Health Statistics and Quality Data Review, SAMHSA (2013);
incorporated by reference in its entirety).
pathophysiology have long been suspected and substantiated in the recent years (Goldwaser et al., Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link between Diabetes Mellitus and Alzheimer's Disease. J Alzheimers Dis. (2016 Aug 1);
incorporated by reference in its entirety). In several large post-mortem series, more than a third of all subjects clinically diagnosed with typical AD showed evidence of cerebrovascular disease and had to be re-classified as mixed dementia (Grandal et al., Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in a psychogeriatric clinic, Neurologia (2016); incorporated by reference in its entirety). From a clinical perspective, it is therefore desirable to extend AD
therapy beyond currently approved drugs and mechanisms, and also address the cognitive impairment by optimizing a latent diabetic metabolic situation or the fairly frequent Type 2 diabetes in the elderly subjects. Indeed, glycemic control is thought to have an impact on the severity of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep, 16 (9):87 (2016); incorporated by reference in its entirety). Due to the specific anti-diabetic actions of a compound of Formula I described above, in one embodiment, the present inventon provides benefit on both, symptoms and disease progression in AD, and in cognitive impairment of mainly vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment, etc.).
Best-practice treatment guidelines promote initial consideration of comorbidities and reduction of dopaminergic therapy. However, these approaches are often insufficient, and few other therapeutic options exist.
When correctly diagnosed, successful treatment is possible < 50% of diagnosed patients and as many as 10-15% of patients eventually die as a result of suicide (NIMH 2002).
remains less than ideal. Most individuals still have breakthrough episodes or significant residual symptoms while on medication (NIMH 2002). In addition, functional deficits often remain even when patients are in remission (NIMH 2002). Because many patients with BP
remain symptomatic, even while fully adherent to their medication regimens, the need for greater understanding of the pathogenesis of this illness from the research on the pharmacological mechanisms of bipolar medications is all the more urgent. The major medication therapy of BPs is mood stabilizers unless the pharmacology mechanisms are not clear yet. Common neuroprotective effects of mood stabilizers play a role of brain cell dysfunction in BP, and the dysfunction may eventually cause neuron loss. Volumetric neuroimaging, now increasingly assessing potential involvement of different brain structures in mood regulation, could be applied to test neuroanatomical models of mood disorders. Imaging studies suggested that ongoing neuronal atrophy accompanies BP. For instance, PET images of the cerebral blood flow and the rate of glucose metabolism regarding as brain activity detected the reduced activity in the subgenual prefrontal cortex during the bipolar depression. This decrement in activity was, in part, at least explained by a corresponding reduction of cortical volume, as same as magnetic resonance imaging demonstration of the mean gray matter volume. In BP, abnormalities of the third ventricle, frontal lobe, cerebellum, and possibly the temporal lobe are also noted.
Benign (not cancerous) tumors may grow and press on nearby areas of the brain, but rarely spread into other tissues. Malignant (cancerous) tumors are likely to grow quickly and spread into other brain tissue. A tumor that grows into or presses on an area of the brain may stop that part of the brain from working the way it should, whether the tumor itself is benign or malignant, and will then require treatment. The most common type of brain tumor seen does not originate from the brain tissue itself, but rather are metastases from extracranial cancers such as lung cancer and breast cancer. Brain tumors include neurofibromatosis type 1 or 2, von Hippel-Lindau disease, tuberous sclerosis, Li-Fraumeni syndrome, Turcot syndrome type 1 and type 2, Klinefelter syndrome, and Nevoid basal cell carcinoma syndrome. Neuroblastoma is cancer found in developing nerve cells, usually in children under 10 years of age. Almost 90% of cases are diagnosed by the age of 5.
Different factors can affect the type of neuroblastoma a child has and their prognosis.
the extent of the condition; and other individual factors. Generally, treatment for patients with cancer of the brain or spinal cord includes surgery, chemotherapy, radiation therapy, and/or steroids to treat and prevent swelling, especially in the brain; anti-seizure medication to treat and prevent seizures associated with intracranial pressure; placement of a shunt (to help drain excess fluid in the brain);
lumbar puncture/spinal tap (to measure pressure in the spinal cord and brain);
bone marrow transplantation; rehabilitation (to regain lost motor skills and muscle strength); and/or antibiotics (to treat and prevent infections). Chemotherapy is the use of anticancer drugs to treat cancerous cells. In most cases, chemotherapy works by interfering with the cancer cell's ability to grow or reproduce. These drugs may be given into a vein or by mouth, as a tablet.
11(8): e0161092 (2016); Van der Schyf CJ. Psychotropic Drug Development Strategies that Target Neuropsychiatric Etiologies in Alzheimer's and Parkinson's Diseases. Drug Dev Res. 77: 458-468 (2016)).
Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Peters ME et al.
Neuropsychiatric Symptoms as Predictors of Progression to Severe Alzheimer's Dementia and Death: The Cache County Dementia Progression Study. Am J Psychiatry 172: 460-465 (2015)).
Hary Rev Psychiatry 23: 377-393 (2015)). Therefore, a strategy aimed at simultaneously targeting multiple etiologies of a disease (hence, multiple drug targets) constitutes the best approach in the development of treatment strategies for a range of diseases including but not limited to AD (Nikolic K et al. Drug design for CNS diseases: polypharmacological profiling of compounds using cheminformatic, 3D-QSAR and virtual screening methodologies. Front Neurosci 10: 265 (2015)).
Prog Neurobiol 72(3):195-221 (2004)). Therefore, impairments in different circuits underlie the emergence of different BPSD symptoms. Heterogeneity of the clinical presentations of neurodegenerative disorders is determined by the predominant location of the pathology (i.e. by affected networks). For example, the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex are more affected in apathetic patients, and the medial orbital frontal cortex in disinhibited patients with bvFTLD (e.g., Massimo et al. Dement Geriatr Cogn Disord 27:96-104 (2009)).
receptors that are present across various cortical areas (van Dyck CH et al.
PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with 118Flaltanserin. J Nucl Med 41(2):234-41 (2000)).
Thalamus plays a central role in ongoing cortical functioning. Nat Neurosci 19(4):533-41 (2016)).
11(8): e0161092 (2016)).
symptoms occurs in various combinations or clusters. For example, a frequent AD cluster could e.g. be aggression, agitation, wandering, repetitiveness, while a frequent Vascular Dementia cluster could e.g. be confusion and restlessness, but the frequency and severity of NPI items is subject to change, e.g. from day to day, but especially during disease progression (Kazui et al. Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Johnson DK et al. Neuropsychiatric profiles in dementia. Alzheimer Dis Assoc Disord 25(4): 326-332 (2011)). As a given patient may present such a cluster of several symptoms of clinical relevance at once, there is a high medical need in treatments that can target various clusters of symptoms or the entire range of BPSD symptoms, irrespective of any currently prevailing pathophysiological hypothesis on the disease.
Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos CG et al.
Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al.
The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). Prevalence of hallucinations is also low in the general population, in people with normal cognitive aging (0.4-0.6%) but is increased in subjects with MCI (0.6-1.3%) and dementia (10.5-16.0%) (Geda YE et al. The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study.
Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71(2016)).
adverse events and showed a markedly increased death rate when used off-label in dementia. Hence, the FDA issued a "black box" warning against their off-label use outside schizophrenia which leaves little therapeutic options to treat such BPSD symptoms in dementia. On this background, a completely different class, namely 5-HT2A receptor antagonists and inverse agonists demonstrated an antipsychotic-like efficacy profile in preclinical studies (Weiner et al. 5-hydroxytryptamine2A
receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299(1):268-76 (2001)).
Several 5-HT2A receptor antagonists and inverse agonists have been in development for neuropsychiatric indications and there were reports of beneficial antipsychotic effects obtained with compounds such as eplivanserin (Meltzer HY et al. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161:
975-84 (2004)). 5-HT2A receptor inverse agonist pimavanserin significantly reduced psychotic symptoms, which includes hallucinations and delusions, in patients with moderate to severe Parkinson's disease (Cummings J et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383: 533-40 (2014)) and has been FDA
approved specifically for the treatment of these symptoms in PDD. In patients with Alzheimer's disease dementia, HTR2A T102C polymorphism is a significant risk factor for psychosis with an allelic OR of 2.191 for C allele that increased to 5.143 for the homozygous CC
genotype (Ramanathan S, Glatt SJ. Serotonergic system genes in psychosis of Alzheimer dementia: meta-analysis. Am J
Geriatr Psychiatry 17(10):839-46 (2009)).
Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan.
Pharmacol Biochem Behav 40(2):381-6 (1991)). Meta-analysis of the randomized controlled studies of another NMDA
receptor channel blocker, memantine, in patients with Alzheimer' s disease indicated that memantine induces significant improvement in delusions (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer' s disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
scale. Prevalence of agitation and aggression is low in general population, in people with normal cognitive aging (2.8-2.9%) but is increased in subjects with MCI (9.1-11.3%) and dementia (30.3-40%) (Geda YE et al.
The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008);
Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). So this NPI item is one the most prevalent and at the same time difficult to treat clinical BPSD symptom.
allele (Banlaki Z et al. Polymorphism in the serotonin receptor 2a (HTR2A) gene as possible predisposal factor for aggressive traits. PLoS One 10(2):e0117792 (2015)). In a case-control study in Chinese subjects with AD, aggression in AD was significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam LC et al. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)).
314(12):1242-54 (2015))). A meta-analysis of randomized controlled studies of another nonselective NMDA
receptor channel blocker, memantine, in patients with Alzheimer' s disease indicated that also memantine induces significant improvement in agitation/aggression (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer' s disease: a meta-analysis.
Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos CG et al.
Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al.
The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
Psychiatry 173(8):816-26 (2016)). Dextromethorphan given in combination with quinidine also exerts antidepressant action in humans (Murrough JW et al. Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial.
J Affect Disord 218:277-283 (2017)). Dextromethorphan is not a selective NMDA
receptor channel blocker and is more potent at serotonin and norephinephrine transporters as well as sigma-1 receptors that may contribute to therapeutic effects of dextromethorphan (Stahl SM. Mechanism of action of dextromethorphan/quinidine: comparison with ketamine. CNS
Spectrums 18: 225-227 (2013)). While monoamine transporters are targeted by most currently used antidepressants, sigma-1 receptors have also been found to contribute to antidepressant-like effects of dextromethorphan in laboratory animals (Nguyen L et al. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One 9(2):e89985 (2014)).
(2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA
288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). In a case-control study in Chinese subjects with AD, apathy in AD was significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam LC et al. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)).
Apathy is a symptom frequently seen in patients with schizophrenia and belongs to the group of negative symptoms. 5-HT2A receptor antagonists reduce the severity of negative symptoms in patients with schizophrenia (Davidson M et al. Efficacy and Safety of MIN-101:
A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. Am J Psychiatry DOI:
10.1176/appi.ajp.2017.17010122 (2017); Meltzer HY et al. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161(6):975-84 (2004)).
(2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA
288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
NeuroImage 47: S39¨S41 (2009)). 5-HT2 receptor antagonist serazepine (CGS-15040A) has shown efficacy in clinical trials in patients with generalized anxiety disorder (Katz RJ et al.
Serotonergic (5-HT2) mediation of anxiety-therapeutic effects of serazepine in generalized anxiety disorder. Biol Psychiatry 34: 41-44 (1993)).
Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs 2(8):1112-9 (2001)), dextromethorphan was observed to induce anxiolytic-like effects in laboratory animals within a certain dose range (Dere E et al. NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice. Behav Pharmacol 14(3):245-9 (2003)). Preclinical anxiolytic effects of dextromethorphan may be related not only to the inhibition of NMDA receptor function but also to interaction with the sigma-1 receptors (Kamei H
et al. (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites. EurJ Pharmacol 299(1-3):21-8 (1996)). In patients with AD, treatment with another nonselective NMDA receptor channel blocker, memantine, significantly decreases in the scores of NPI subscale for anxiety (Ishikawa I
et al. The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease.
Acta Neuropsychiatr 28(3):157-64 (2016)).
288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
nonselective 5-HT2A
receptor agonist psilocybin significantly reduced [11Clraclopride BP in the ventral striatum that correlated with depersonalization associated with euphoria (Vollenweider FX et al. 5-HT
modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man -- a PET
study with [11Clraclopride. Neuropsychopharmacology 20(5):424-33 (1999)).
Preclinical data have indicated that the majority of prefrontal cortical pyramidal neurons that project to the dorsal raphe nuclei and ventral tegmental area
Cereb Cortex 19:1678-86 (2009)). Consequently, blockade of prefrontal 5-HT2A
receptors may modulate pyramidal neurons projecting to the midbrain and thereby inhibit the dopaminergic system in the midbrain (Erbdrup BH et al. Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin Investig Drugs 20(9):1211-1223 (2011)).
DOpaminergic midbrain system is also under control of cholinergic projections such as those originating in habenula and activity of these projections are modulated by a3r34-containing nicotinic acetylcholine receptors (McCallum SE et al. a3r34 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo. Neuropharmacology 63(3):434-40 (2012)). Antagonism at a3r34-containing nicotinic acetylcholine receptors is associated with various effects ascribed to reduced dopamine tone (Maisonneuve IM, Glick SD.
Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol Biochem Behav 75(3):607-18 (2003)). a334-containing nicotinic acetylcholine receptors are one of the main targets of dextromethorphan (Taylor CP et al. Pharmacology of dextromethorphan:
Relevance to dextromethorphan/quinidine (Nuedexta0) clinical use. Pharmacol Ther 164:170-82 (2016)).
288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
system underlie impulse control and preclinical studies suggest that the 5-HT2A receptor regulates impulsive behavior, including both inherent and induced behavioral disinhibition (Anastasio NC et al. Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and ***e-evoked behavioral disinhibition in rats. Behav Pharmacol 22(3):248-61 (2011)).
et al. The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients. J Psychiatr Res 46(1):44-9 (2012)). Humans with the A/A genotype of the HTR2A 1438A/G polymorphism have higher scores of maladaptive impulsivity (Tomson K et al. Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity:
Dependence on cholesterol levels. J Affect Disord 206:23-30 (2016)). From a neuroanatomical perspective, neocortex is known to be rich in 5-HT2A receptors and behavioral disinhibition in neurodegenerative diseases such as behavioral variant frontotemporal dementia is correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula (Santillo AF et al. Grey and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease. PLoS One 11(10):e0164122 (2016)).
may occur in association with a variety of neurological diseases such as amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. PBA is a disinhibition syndrome, in which pathways involving serotonin and glutamate are disrupted (Ahmed A, Simmons Z. Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag 9:483-9 (2013)). Meta-analysis of the randomized controlled studies of another nonselective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease indicated that memantine induces significant improvement in disinhibition (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer' s disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
an emerging role for the 5-HT2A serotonin receptor in the modulation of emotion-based actions?
Mol Neurobiol 48(3):841-53 (2013)).
Neurol Ther 17;3(1):15-28 (2014)). In patients with AD, treatment with another nonselective NMDA
receptor channel blocker, memantine, significantly decreases the scores of NPI
item for irritability/lability (Ishikawa I et al. The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-64 (2016)). Meta-analysis of the randomized controlled studies of memantine in patients with Alzheimer' s disease indicated that memantine was superior to control in irritability/lability (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer' s disease:
a meta-analysis.
Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
receptor polymorphism such as T102C (Lam LC et al. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004);
Pritchard AL et al. Role of 5HT 2A and 5HT 2C polymorphisms in behavioural and psychological symptoms of Alzheimer's disease. Neurobiol Aging 29(3):341-7 (2008)).
et al. Striatal glutamatergic mechanisms and extrapyramidal movement disorders. Neurotox Res 5(1-2):139-46 (2003)) and antagonism at a334-containing receptors (Maisonneuve IM, Glick SD.
Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol Biochem Behav 75(3):607-18 (2003)), two of the receptor targets of dextromethorphan (Taylor CP
et al. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta0) clinical use. Pharmacol Ther 164:170-82 (2016)).
Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71(2016)).
Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383: 533-40 (2014)). Another 5-HT2A receptor inverse agonist, eplivanserin, has demonstrated clinical efficacy in patients with insomnia (European Medicines Agency.
Withdrawal Assessment Report for Sliwens (Eplivanserin), March 18, 2010, London.
EMA/CHMP/90435/2010).
receptor channel blocker, memantine, in patients with Alzheimer's disease indicated that memantine induces significant improvement in nighttime disturbance/diurnal rhythm disturbances (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer' s disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
In patients with AD, memantine was effective in reducing fragmented sleep and polysomnography revealed longer total sleep, increases in sleep efficiency and time spent in stage II, and decreases in nocturnal awakening, the periodic limb movement index, and time spent in stage I
(Ishikawa I et al. The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-64 (2016)).
Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71(2016)).
receptor (HTR2A) has been implicated as a functional candidate in many neuropsychiatric phenotypes including eating disorders (Norton N, Owen MJ. HTR2A: association and expression studies in neuropsychiatric genetics. Ann Med 37(2):121-9 (2005)). Eating behavior and appetite are also modulated by one of the receptor target's of dextromethorphan, serotonin transporter, that is affected in patients with eating disorders (Spies M et al. The serotonin transporter in psychiatric disorders: insights from PET imaging. Lancet Psychiatry 2(8):743-55 (2015)).
symptoms; iv) a single TMA may not produce a maximally possible therapeutic benefit against even a single BPSD symptom or symptom cluster.
Several neuropsychiatric diseases and syndromes such as Alzheimer' s disease and behavioral and psychological symptoms of dementia involve dis-regulation of glutamatergic, cholinergic, serotoninergic and norepinephrinergic neurotransmitter systems. Accordingly, In another embodiment, the composition comprises an NMDA receptor antagonist such as ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone and dextromethorphan (Jamero et al., The Emerging Role of NMDA Antagonists in Pain Management, US
Pharm.
36(5):HS4-HS8 (2011); Sang, NMDA-receptor antagonists in neuropathic pain:
experimental methods to clinical trials, J Pain Symptom Manage. 19 (1 Suppl) S21-5 (2000);
incorporated in entirety herein by reference). In another embodiment, the composition is a combination of a compound of Formula I, and ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, or dextromethorphan. The compound of Formula I forms the combination as mixture, complex, conjugate, compound with covalent bond, or a salt.
abnormalities, behavior, cognition, and reduce seizures, as well as improve breathing abnormalities, motor capabilities, bone density, and GI dysfunction. Another embodiment is the treatment of a person in need thereof comprising administering a composition comprising DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTm to improve EEG abnormalities, behavior, cognition, and reduce seizures, as well as improve breathing abnormalities, motor capabilities, bone density, and GI dysfunction. Another embodiment is a treatment of a person in need thereof comprising administering a composition comprising DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm in the treatment of other diseases and conditions, including involuntary emotional expression disorder (IEED) or pseudobulbar affect (PBA), neurodegenerative diseases, neuropathic pain, and brain injuries.
chlorpheniramine), decongestants (e.g., pseudoephedrine) and/or expectorants (e.g., guaifenesin).
are catalyzed by enzymes in the related CYP3A family. Conjugates of DO and 3-hydroxymorphinan can be detected in human plasma and urine within hours of its ingestion. DO
is a substance most notable for its psychoactive effects.
inhibits responses to 5-HT mediated by 5-HT2A receptors such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. SGL (MCI-9042) was shown to have the same affinity as ritanserin for 5-HT2A receptors (Nishio et al., Binding affinity of a compound of formula I or sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes.
Arch Int Pharmacodyn Ther. 331(2):189-202 (1996 March-April); incorporated by reference in entirety). The blockade of 5-HT2A receptors can inhibit thrombus formation, suppresses platelet aggregation and inhibits vascular smooth muscle cell proliferation (Pertz et al., In-vitro pharmacology of a compound of Formula I and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT
contractions in rat tail artery. J Pharm Pharmacol. 47(4):310-6 (1995 April); incorporated by reference in entirety).
Accordingly, an embodiment is a method of treatment of a patient in need thereof comprising administering a composition comprising a compound of Formula I and a compound of Formula II, or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm.
cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, Volume 13, Issue 7 (2004);
incorporated by reference in entirety).
(Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta0) clinical use. Pharmacol Ther. 164:170-82 (2016 August);
incorporated by reference in its entirety). Therefore, another embodiment is a method of reducing adverse effects of DEX
during treatment of a patient in need thereof comprising the step of administering a pharmaceutical composition comprising DEX and one or more agents selected from the group comprising 5-HT2A
receptor antagonist/inverse agonist, and CYP2D6 inhibitor. In another embodiment, the agent is an agent having properties of both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor. In another embodiment, the agent is an agent having properties of both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor. In another embodiment, the agent is a compound of Formula I and a compound of Formula II, or DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTm.
incorporated by reference in entirety), a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor.
This enzyme is also important in the metabolism of other drugs that are commonly prescribed to patients with psychiatric disorders, e.g., tricyclic antidepressants (nortriptyline, desipramine, amitriptyline, imipramine, and clomipramine) and selective serotonin reuptake inhibitors, including fluoxetine and paroxetine (Taylor and Lader,1996; Sproule et al., 1997; incorporated by reference in entirety).
Drugs that inhibit these enzymes would be expected to cause increases in the plasma concentration of co-administered antipsychotic drugs (Goff, 1993; Ereshefsky, 1996;
Michalets, 1998;
incorporated by reference in entirety). These increases may, in turn, lead to the development or aggravation of antipsychotics-induced side effects including cardiac toxicity, anticholinergic side effects, or orthostatic hypotension (Ereshefsky, 1996; Desta et al., 1999;
incorporated by reference in entirety).
quinidine. The estimated mean IC50 values for thioridazine and perphenazine were 2.7 + 0.5 and 1.5 0.3 micro M, respectively. The IC50 of quinidine, a potent CYP2D6 inhibitor, was estimated to be 0.52 + 0.2 micro M under these conditions. The estimated IC50s of chlorpromazine, fluphenazine, and haloperidol were 9.7, 16.3, and 14.4 micro M, respectively. Cisthiothixene, clozapine, and risperidone exhibited weaker inhibition than the other drugs tested, with mean ICsos estimated to be 136.6, 92.2, and 39.1 micro M, respectively (Shin et al., Effect Of Antipsychotic Drugs on Human Liver Cytochrome P-450 (Cyp) Isoforms in Vitro: Preferential Inhibition of CYP2D6, Drug Metabolism And Disposition, Vol. 27, No. 9 (1999); incorporated by reference in its entirety).
receptor antagonism and 2D6 inhibition. In another embodiment, the invention is a combination of a 5HT2A receptor inverse agonist and a CYP2D6 inhibitor providing a therapeutic advantage of the simultaneous 5HT2A receptor inverse agonism and 2D6 inhibition. A compound of Formula I and a compound of Formula II; or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm provides a unique therapeutic advantage by combining both CYP2D6 inhibition and 5HT2A receptor inverse agonism to improve the magnitude of the therapeutic response to DEX. Thus, Formula I and a compound of Formula II; or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTm avoids potential health risks associated with the concomitant use of an anti-arrhythmic drug quinidine with DEX.
Accordingly, an embodiment is a composition comprising Formula I and a compound of Formula II; or DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTm.
or, DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTm to a subject in need of DEX and/or a compound of Formula I, DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTm treatment, wherein the subject is at risk of experiencing the adverse event as a result being treated with DEX and/or a compound of Formula I, DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTM.
plasma level is lower than the DO plasma level that would have been achieved by administering the same amount of DEX administered without a compound of Formula I for eight consecutive days.
is present in the body of the subject at the same time as a compound of Formula I.
comprising administering a compound of Formula I and a compound of Formula II;
or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTm in conjunction with administration of DEX to a subject in need of treatment for a cough.
administered without a compound of formula I, for five consecutive days.
administered without a compound of formula I, for six consecutive days.
comprising, co-administering a compound of formula I, with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering a compound of formula I, with DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without a compound of formula I.
comprising, co-administering a compound of formula I, with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering a compound of formula I, with DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without a compound of Formula I.
comprising, co-administering a compound of formula I, with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering a compound of formula I, with DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without a compound of Formula I.
receptor antagonist/inverse agonist for the use in combination with DEX in a subject in need thereof.
Neuropharmacology.
36: 241-250 (1997); Popik et al., Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine. J. Pharmacol. Exp. Ther. 280: 854-865 (1997); Popik et al., Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists. Neuropharmacology. 37: 1033-1042 (1998);
incorporated by reference in its entirety) and may attenuate not only the physical but also affective and motivational components of abstinence states, as well as craving (Cornish et al. A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83(2002);
incorporated by reference in entirety). By reducing withdrawal symptoms, such medications should be beneficial for the patients during the acute detoxification phase of treatment for opioid dependence (Cornish et al., A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83 (2002);
incorporated by reference in entirety).
Neurosci. 16: 274-282 (1996); incorporated by reference in entirety). Excitatory amino acids are involved in the mediation of many neurochemical and behavioral effects resulting from chronic exposure to abusing drugs, some of which can be prevented or reversed using glutamatergic antagonists (Inturrisi, Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependence. Semin. Neurosci.
9: 110-119 (1997); incorporated by reference in entirety). Continued self-administration of abusive drugs, including opioid, results in an overstimulation of dopamine in the brain reward centers and an increased release of excitatory amino acids including glutamate leading to the development of tolerance and dependence which could be blocked by glutamate antagonists (Herman et al., Clinical medication development for opiate addiction: focus on nonopioids and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention.
Semin. Neurosci. 9: 158-172 (1997); incorporated by reference in entirety).
Accordingly, an embodiment is a method of treating a subject in need of treatment for disorders or diseases associated with addiction and substance abuse resulting from opioid tolerance and dependence by amelioration of opiate withdrawal symptoms and relapse prevention comprising administration of DEX and Formula I, or DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTm, or DERAPHANTM.
305(1):212-8 (2003); Zhang et al., Neuroprotective effect of dextromethorphan in the MPTP
Parkinson's disease model: role of NADPH oxidase. FASEB Journal. 18(3): 589-91 (2004); Zhang et al., 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB Journal. 19(3): 395-7 (2005); incorporated by reference in ientirety). 1-10 micro M DEX protected dopamine neurons against lipopolysaccharide (LPS)-induced reduction of dopamine uptake in rat primary mixed mesencephalic neuron-glia cultures.
Morphologically, in LPS-treated cultures, besides the reduction of an abundance of dopamine neurons, the dendrites of the remaining dopamine neurons were significantly less elaborative than those in the controls. In cultures pretreated with DEX (10 micro M) before LPS
stimulation, dopamine neurons were significantly more numerous and the dendrites less affected. Significant neuroprotection was observed in cultures with DEX added up to 60 minutes after the addition of LPS. Thus, DEX significantly protects monoamine neurons not only with pretreatment but also with post-treatment (Zhang et al., Neuroprotective effect of dextromethorphan in the MPTP
Parkinson's disease model: role of NADPH oxidase. FASEB Journal, 18(3): 589-91 (2004);
incorporated by reference in entirety). Animal studies using both LPS and MPTP
PD models also show potent protective effect of DEX (Zhang et al., Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB Journal, 18(3): 589-91 (2004); incorporated by reference in entirety). Accordingly, an embodiment is a method of treating a subject in need of a treatment for Parkinson's disease comprising administration of DEX and Formula I, or DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTm, or DERAPHANTM.
The activation of the HPA axis increases the products of GC as potent immunomodulatory hormones (Freier et al., A mechanism of action for morphine-induced immunosuppression:
corticosterone mediates morphine-induced suppression of natural killer cell activity. J Pharmacol Exp Ther 270(3): 1127-33 (1994); Mellon et al., Role of central opioid receptor subtypes in morphine-induced alterations in peripheral lymphocyte activity. Brain Res 789(1): 56-67 (1998);
incorporated by reference in entirety). Accordingly, an embodiment is a method of treating a subject in need of treatment for a disorder or disease thereof comprising administration of DEX
and Formula I, or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTM wherein the disorder or disease is opioid dependence. The dosage of up to about 500 mg/day DEX is suggested, including doses of 120, 240, and 480 mg/day of DEX for heroin addicts undergoing withdrawal. DEX at high doses caused mild elevations of heart rate, blood pressure, temperature, and plasma bromide (Cornish et al., A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients.
Drug & Alcohol Dependence. 67(2): 177-83 (2002); incorporated by reference in entirety).
Particularly among Han Chinese in Taiwan, DEX has been reported to have quite different "dextromethorphan metabolic enzyme CYP2D6" from that of Western population (Yeh et al., Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes. J. Biomed. Sci. 10: 552-564 (2003); incorporated by reference in entirety).
Psychiatry Investig. 6(1): 13-8 (2009); O'Brien et al., Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord. 90(2-3): 263-7 (2006); Brietzke et al., Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J
Affect Disord. 116(3): 214-7 (2009); incorporated by reference in entirety).
levels of IL-1 beta receptor and neuroinflammatory markers inducible nitric oxide synthase (iNOS) and c-fos were found (Rao et al., Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol. Psychiatry.
15(4): 384-92 (2010);
incorporated by reference in entirety). Taken together, the imbalance of the immune system, subsequently leading to the neuronal inflammatory response, might be related to the progression of the brain atrophy and aggravated BP symptoms. BP treatment with immune-targeted therapies showed antidepressant effects. For example, open-label acetylsalicylic acid when added to fluoxetine led to increased remission rates in individuals with major depression who were previously non-responsive to fluoxetine monotherapy (Mendlewicz et al., Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int. Clin. Psychopharmacol. 21(4): 227-31 (2006); incorporated by reference in entirety).
reduction in brain volume in BP patients was found to be largely suppressed by chronic treatment with Valproate (VPA) resulting in neuroprotective effects, as VPA renders neurons less susceptible to a variety of insults (Chen et al., Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry. 11(12):1116-1125 (December 2006); incorporated by reference in entirety) and even stimulates neurogenesis in the adult rodent brain. VPA induces cytoprotective proteins like Bc1-2, glucose-regulated protein 78 (Grp78), brain-derived neurotrophic factor (BDNF) and heat shock protein 70.
Moreover, VPA
promotes neurite outgrowth, while VPA at therapeutic levels was reported to inhibit histone deacetylase (HDAC), an enzyme that catalyzes the removal of the acetyl group from lysine residues of histones, promoting local, neuronal BDNF biosynthesis. Accordingly, an embodiment is a method of treating a subject in need of treatment for a disorder or disease thereof comprising administration of DEX and a compound of Formula I, or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHANTm, wherein the disorder or disease is BP.
a. administering DEX; and b. administering a compound of Formula I, to the subject.
inverse agonist, such as a compound of formula I in conjunction with administration of DEX to a subject in need of treatment for a neuropsychiatric disorder.
Extensive metabolizers of DEX are a significant portion of the human population. DEX can, for example, be metabolized to DO.
The low plasma concentrations of DEX can limit its clinical utility as a single agent for extensive metabolizers, and possibly intermediate metabolizers, of DEX. Some antidepressants, such as a compound of Formula I inhibit the metabolism of DEX, and can thus improve its therapeutic efficacy. Similarly, antidepressants may allow DEX to be given less often, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times a day, or twice a day instead of four times a day, without loss of therapeutic efficacy.
Patients with apathy suffer from decreased daily function and specific cognitive deficits and rely on families to provide more care, which results in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have multiple neuroanatomical correlates that implicate components of frontal subcortical networks. Despite the profound effects of this common syndrome, only a few instruments have been designed to specifically assess apathy, and these instruments have not been directly compared. Assessment of apathy in AD requires clinicians to distinguish loss of motivation from loss of ability due to cognitive decline. Although apathy may be misdiagnosed as depression because of an overlap in symptoms, current research has shown apathy to be a discrete syndrome.
Distinguishing apathy from depression has important treatment implications because these disorders respond to different interventions.
assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment, the Journal of Geriatric Psychiatry, Volume 17, Issue 12, Pages (December 2002); Landes et al., Apathy in Alzheimer's Disease, the Journal of American Geriatric Society, Volume 49, Issue 12, Pages 1700-1707 (December 2001); Malloy et al., Apathy and Its Treatment in Alzheimer's Disease and Other Dementias, Psychiatric Times, Vol.
XXII, Issue 13 (November 01, 2005); incorporated by reference in entirety). Apathy can be the result of damage to one or more areas of the brain such as the frontal cortex, the thalamus, striatum and the amygdala.
In most cases direct damage to the frontal lobes or the subcortical nuclei that have connections to the frontal lobes, cause apathy. Apathy associated with Alzheimer's disease is very difficult to treat. Antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors etc. alleviated apathy only to some degree.
and Formula I, or DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTm ; and one or more of antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, dopaminergic agents. Another embodiment is a combination of DEX and Formula I, or DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTm and one or more of donepezil, memantine, amantanidine, bupropion, ropinirole, methylphenidate, amphetamine, modafinil, metrifonate, tacrine, galantamine, rivastigmine, nefiracetam, ginkgo biloba extract, etc.
(Ruthirakuhan et al., Pharmacological interventions for apathy in Alzheimer's disease (Protocol), Cochran Database of Systemic Studies, 2016, Issue 5. Art. No.: CD012197, Published by John Wiley & Sons, Ltd.; Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease: A Systematic Review Across Modalities, Journal of Geriatric Psychiatry and Neurology, Vol 30, Issue 1, 2017; references are incorporated by reference in entirety).
Reference ID: 3096907; Guidance on Donepezil Hydrochloride, Finalized Aug 2017, incorporated by reference in entirety).
receptor antagonist/inverse agonist such as a compound of formula I includes, but is not limited to, drug dependence, addiction to ***e, psychostimulants (e.g., crack, ***e, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites.
Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.
receptor antagonist/inverse agonist such as a compound of formula I include, but are not limited to, disorders involving intellectual deficits such as vascular dementia, Alzheimer's type dementia, Lewy Body Dementia, Fronto-Temporal Lobar Degeneration, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, dementia, coma, lowering of attention, apathy, and speech disorders.
receptor antagonist/inverse agonist such as a compound of formula I include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Fronto-Temporal Lobar Degeneration (FTLD).
and a 5-HT2A
receptor antagonist/inverse agonist such as a compound of formula I include, but are not limited to Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barre syndrome, and spastic paraplegia.
receptor antagonist/inverse agonist such as a compound of formula I, a derivative, a metabolite or prodrug of any of these compounds include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.
lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoarthosis, axial spondyloarthritis including ankylosing spondylitis, etc.
include, but are not limited to, a compound of formula I, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, etc., or a metabolite or prodrug of any of these compounds, or a pharmaceutically acceptable salt of any of these compounds.
metabolism. Thus, a compound of formula I, including a form of a compound of formula I, that is rapidly converted in the body (such as a salt, hydrate, solvate, polymorph, etc.), is a prodrug of a compound of formula I.
to about 160%, about 160% to about 170%, about 170% to about 180%, about 180%
to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to a compound of formula I alone.
to about 160%, about 160% to about 170%, about 170% to about 180%, about 180%
to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to as compared to DEX alone.
alternate solid forms, such as polymorphs, solvates, hydrates, etc.;
tautomers; deuterium-modified compounds, such as deuterium-modified DEX and a compound of formula I; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein. Examples of deuterium modified DEX and a compound of formula I, include, but are not limited to, those shown below.
For example, DEX and a compound of formula I, may be dispersed within each other or dispersed together within a vehicle. A dispersion may include a mixture of solid materials wherein small individual particles are substantially one compound, but the small particles are dispersed within one another, such as might occur if two powders of two different drugs are blended with a solid vehicle material, and the blending is done in the solid form. In some embodiments, DEX and a compound of formula I, may be substantially uniformly dispersed within a composition or dosage form. Alternatively, DEX and a compound of formula I, may be in separate domains or phases in a composition or dosage form. For example, one drug may be in a coating, and another drug may be in a core within the coating. For example, one drug may be formulated for sustained release and another drug may be formulated for immediate release.
hydrochloride could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL') to form an admixture of blended powders. This could then be combined with immediate release DEX in a single tablet.
For example, they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.
ratio of 0.1 indicates that the weight of DEX is 1/10 that of a compound of formula I. A ratio of 10 indicates that the weight of DEX is 10 times that of a compound of formula I.
(w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1%
(w/v), about 0.1%
(w/v) to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10%
(w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30%
(w/v), about 30%
(w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of DEX.
plasma level on the first day may be reduced by at least 5% as compared to the DO plasma level that would be achieved by administering the same amount of DEX without a compound of formula I.
without a compound of formula I, for five consecutive days.
that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1,000 times, the plasma level that would be achieved by administering the same amount of DEX
without a compound of formula I for eight consecutive days.
(w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v) to about 3%
(w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30%
(w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of a compound of Formula I or any amount of a compound of Formula I, in a range bounded by, or between, any of these values.
in a range bounded by, or between, any of these values.
(w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20%
(w/v), about 20%
(w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50%
(w/v) of DEX and a compound of Formula I combined, or any amount in a range bounded by, or between, any of these values. Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70%
(w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20%
(w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30%
(w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%
(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80% (w/w), about 80%
(w/w) to about 90% (w/w) of DEX and a compound of Formula I combined, or any amount in a range bounded by, or between, any of these values. In some embodiments, the weight ratio of DEX
to a compound of Formula I in a single composition or dosage form may be about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values.
may be administered once daily; or twice daily or every 12 hours, or three times daily in an amount that is about half or one-third, respectively, of the daily dose.
and/or 2) about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day of DEX, are administered to a subject in need thereof.
For oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coating, for instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially nontoxic in the amounts employed.
dispersion can also have an oil dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof.
Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
symptoms increases with the disease progression (e.g. up to 60% in mild and moderate AD and up to 90% in severe AD).
chronic or intractable pain, ophthalmologic indications associated with retinopathies, anxiety disorders, post-traumatic stress disorder, depression, diabetes mellitus and it's complications like peripheral neuropathies with or without neuropathic pain, Buerger' s disease, Raynaud' s disease, coronary artery disease, angina pectoris, atherosclerosis including CNS like multi-infarct dementia, Vascular Cognitive Impairment, Vascular Dementia or Binswanger's Disease, and nephropathies.
to improve the therapeutic properties of DEX in the treatment of neuropsychiatric disorders.
or pharmaceutically acceptable salts thereof.
receptor antagonist/inverse agonist is an enantiomer of M1 such as (R)-1 -(dimethylamino)-3- (2- (3 -methoxyphenethyl) phenoxy) propan-2-ol) or (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ol), or pharmaceutically acceptable salts thereof.
receptor antagonist/inverse agonist for the use in combination with DEX in subjects in need thereof.
receptor antagonist with potent CYP2D6 inhibitory activity has higher blood-brain barrier penetration.
antagonist are administered in a combined dose, and wherein the amount of DEX administered comprises from about 20 mg/day to about 80 mg/day.
syrups and suspensions, usingcommonly known ingredients and procedures and methods (U54,221,778, U54,762,709, U54,788,055, U54,959,219, U54,996,047, US5,071,646, and US5,186,930; Borodkin, Book chapter: Ion-exchange resin delivery system, in "Polymers for Controlled Drug Delivery", Tarcha, P J, Ed., CRC Press, Boca Raton, 1990;
incorporated by reference in entirety) can be used to formulate the compositions of the invention.
syrups and suspensions, and ommonly known ingredients and procedures to formulate pharmaceutical composition are within the purview of a person skilled in the art, including various known methods (U54,221,778, U54,762,709, U54,788,055, U54,959,219, U54,996,047, US5,071,646, U54,221,778, and US5,186,930; incorporated herein in their entirety by reference) can be used to formulate the composition of the invention.
SYNTHETIC METHODS
tvledll I
iMo2N101111 jíi d'OH
&mgl.
27r,,õ,1:50 ou Compound 50 11C1 ikodonelTHF
hydrochloride tablets needed to achieve acceptable purity, single hetero content must meet the corresponding requirements. US4485258 discloses a synthesis method of the first SGL
hydrochloride, and recrystallized from acetone to obtain, but the experiments show that SGL
hydrochloride poor solubility in acetone, acetone, hydrochloric acid is not suitable as a recrystallization solvent SGL.
CN101239920A disclosed as acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with methanol, ethanol, acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent SGL hydrochloride, the purity of the product can reach 98%. And C2_10 alkanes, C3_10 ketones, C2_10 carboxylic acid esters, Ci_io halogenated alkanes, aromatic hydrocarbons or aromatic derivative at room temperature to the reflux temperature of the hydrochloric acid solubility is small should not alone SGL as a recrystallization solvent, SGL
hydrochloride, and water as a recrystallization solvent or an organic solvent, an aqueous 5% or more cannot be obtained a high purity product. Existing literature does not mention the issue of a single impurity content control.
'A HI .I a 'VI
CO .
HI
CI õ
.
0 H .4''J'OLO/ R, t,1e2N11 MOH X
\1\111,dC
'k 1 CsF
Scheme!!
H
I $1 i 1 1 ! . 1 HO.-------CrLicl -- IH
it ,lad ,CC1 NaHDAIF hle31\ H
hle21\11 Scheme V
Scheme IA 't% 1H Me Ml 0 1 101 ,0_,01 =
0,0,0 U -0,0,0 " ' CIO
' Scheme III .xcio, C-01794 HCI:AcelonelHF Fr I'ql 9,019 CkA CV . H C.,c,A Yo \ i fk SmPoride (R) SGL-E1 .0, (S) Sarno A C(01 130H , H
,1' -/ \ H r Jompound50 Compound5I Civy:2?s, 50õ
SOL-r2t0,),0?r Ali Compound 51 compopid52 , I 1" "
Compound 52 .1%' YCompound 52 I
Compound 51 L\,CI 0 a le,NH ----\ / Me2NH
0,5,0 . 8 _,. __ A 0 H (+)DET TOPrh Tu001-1 `r $ $
c\ sF 1 _________________________ . = 1 0 kCl Scheme 1 I HI . 0 = \ /Br wo, I 0 1 . (raDET
T(O'Pr)4,43o0OH 1 r/IRA7 I _________________________________________________________________________ ria9 NlerNH 1,,., I II t'D
$ ---. 4, Scheme III
Sharpless .ksmetrIc Eposidation OH - uH
li Oyµo D'Od) LyNCC41 Hvyja. \ VON H
p",/y)oc H
PM 13 Al) 1 I
kr,oll Sch PPh3, DEAD i Me2NI4 eme VEITa /
o_ro Shar ss Asymmetric Dihyoxylation Mes I chloride MeeNH
- -'?
Me2NH scheme vili o*,5 I Sarpogrelate, SGL, Compound50 ilACJ,H _õ.
i Scheme IX
Mes I chloride H 'y'll moil r\r -ae Scheme InTlb _____________________________________________ -. '''y Icii *
(R) Sarpogrelate, SGL-El, Compound 51 yjOH
'N' (S) Samogrelate, Su-E2, Compound 52 I
(R) Sarpogrelat, SGL-E1, Compound 51 I
o*o (S) Sarpogrelate, SGL-E2, Compound 52 Ji-lHvyja. _ilYA''' 1,)(0 . ___ HovoH
tr' I Scheme Vffic
Asymmetric synthesis provides by far the most efficient use of one chiral material to prepare another.
The preparation of enantiomerically pure compounds involves use of chiral auxiliaries, chiral reagents or chiral catalysts, or a combination thereof.
Asymmetry, Volume 7, Issue 9, September 1996, Pages 2551-2562; U57230135 B2; Product: (S)-2-Amino-1,2,3,4-tetrahydro-6-methoxy-naphthalene, Chiral Quest Corp; Ager (Ed), CHAPTER I
Chiral Hydroxy Compounds As Ligands In Asymmetric Synthesis, Handbook of Chiral Chemicals, Second Edition; Hu et al., Adventure in Asymmetric Hydrogenation: Synthesis of Chiral Phosphorus Ligands and Asymmetric Hydrogenation of Heteroaromatics, Top Organomet Chem 36:313-354 (2011); Ishihara et al., An extremely simple, convenient, and selective method for acetylating primary alcohols in the presence of secondary alcohols, J. Org. Chem., 58 (15), pp 3791-3793 (1993); Edwards et al., The stereoselective replacement of hydroxyl groups by chlorine, using the mesyl chloride-N,N-dimethylformamide reagent, Carbohydrate Research, Volume 35, Issue 1, Pages 111-129 (July 1974); incorporated by reference in entirety).
SARPODEXTERTm AND SARPODEXAMIDETm
https://chem.libretexts.org/Core/Organic_Chemistry/Amides/Synthesis_of_Amides;
http://www.chemguide.co.uk/organicprops/amides/preparation.html;W01998043961, incorporated by reference in entirety).
W02006136586 A2; U57932294; US 20060046967 Al; U58357723; U58349901;
U58354455;
U59550734; U520160220694; U520160002167; U520150328323; U59090563;
U520140058063; U520130158271; U58288557; U520110274695; W01998043961;
incorporated by reference in entirety).
11-0 PON ....... R-C = +
\044 om=
Scheme XI
chemguide.co.uk/organicprops/alcohols/esterification.html;http://www.organic-chemistry.org/
namedreactions/fischer-esterification.shtm;
http://www.masterorganicchemistry.com/reaction-guide/conversion-of-carboxylic-acids-to-esters-using-acid-and-alcohols-fischer-esterificationi;
http://vigoschools.org/¨mmc3/AP%20Lab/ap%201ab%20documents/Esterfication.pdf;
http://science.jrank.org/pages/2573/Esterification.html https://chem.libretexts.org/Core/Organic_Chemistry/Carboxylic_Acids/Reactivity_ of_Carboxylic Acids/Fischer_Esterification; W01998043961; incorporated by reference in entirety).
SARPODEXTERTm Scheme XIIpd 165 1 Ccrrx <X, (S)-1-01M~mdm)-8-c1-(8-mdhoxyphcoc441);hamy)prommLy1 yor joH (01,..7,..7,93)-11med,1-6,7,8,40,Trydrn-ty-0,46.0mommo Cc------CLe ...deo Ramona, SM.
Compound 50 cir 1 Compound Ind 01-14,11mokkodno)-3-9,(3-modmvolmnAnd/PhoomWMonm-2,1 wIns,..,0s)-11madM-d,7,8,40,10-hmalmiro-5 11-b(m0..) phconadmm,y0 soodonc In another embodiment of preparation of the compositions of the application, the diastereomerically pure SARPODEXTER can be obtained by reacting the racemic sarpogrelate with optically pure dextrorphan (DO-H3, compound 151) under mild esterification conditions to obtain a mixture of diastereomeric esters, compounds 165-166, which can be separated by crystallization and chromatographic techniques mentioned above and the techniques described in this specification to obtain diastereomerically pure SARPODEXTERs 165 and 166.
EXAMPLES
Preparation of SARPODEXAMIDETm Derivatives
4,4,4-trichloro-1 -(3-methoxy-6,7,8,8a,9,10-hexahydro-5 (epiminoethano)phenanthren-11-yl)butan- 1-one
Number: 125-71-3) can be treated with trifluoromethansulfonic anhydride and pyridine at room temperature (as described in Liebigs Ann. Chem. 1986, 336, and W01998043961, incorporated herein in its entirety).
OPTICALLY PURE SARPODEXAMIDE
CC:NCr- H
I Compound 167 Dintorsonnor Sorpodoz-mmdc (5)-1-(dimothyhtmino)-3-(2-(3-melhozyphrenthyl)phrany) propan-2-y1 44(4138.8.5.93)-3-mulhoxy-N-Donuothyl DostromehmiMm homthydro-5//-9.4b-(epiminoulhano) phenanduen-11-y1)-4-ozobulanoele 0 CAS No. 1531-23-3 rAOH
minimum of manliomers &mongrel.
limmumln 80L Scheme XIII
Compound 50 Compound 168 Dielemomor SarpodexAmido (./0-1-(dimethylamino)-.342-(34nothosyphoucthyl)phommy)propon-211 ((41).5,11.5,95)-.3-mothosy-6,7,8,8a,9,10-homhpiro-5 H-9,4b-(mmunmahano)phonanthren-11,y1)-4-ozobutanonte As shown in Scheme XIII, amides (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-y1 4-((4b5 , 8a5 ,95)-3 -methoxy-6,7, 8, 8a,9 ,10-hexahydro -5H-9,4b-(epiminoethano) phenanthren-11-y1)-4-oxobutanoate (Compound 167) and (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)prop an-2- yl 4-((4bS , 8aS ,9 S )-3 -methoxy- 6,7 , 8, 8 a,9,10-hexahydro-5H-9 ,4b-(epiminoethano)phenanthren-11- y1)-4-oxo butanoate (compound 168) can be obtained from sarpogrelate by amidation with N-desmethyl dextromethorphan using HBTU in combination with Hilnig's base in 1-2 h. Reagents such as uronium salt (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino morpholino carbenium hexafluorophosphate (COMU), ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino) acetate (o-NosylOXY), EDCI
and NaHCO3, B(OCH2CF3)3, trimethylaluminium, Lanthanum trifluoromethanesulfonate, ZrOC12 =
8 H20, methanesulfonyl chloride and N-methylimidazole, N,N'-carbonyldiimidazole (CDI), etc. can be used.
OPTICALLY PURE DEX, Formula I, SARPODEXTM, DERADEXTm, or DERAPHANTm SALT
o, orc"
'14}
Compound 169 o' o 0 Dextromethorphano. Diatereomer (S) Sarpodex salt S OH aqueous medium o Sarpogre6te Racemate (SGL) Compound 50 Scheme XIV H
Compound 170 Diatereomer (R)Sarpodex salt Compound 50 and compound 149 form a diastereomeric salt mixture of dextromethorphan (S)-4-((I -(dimethylamino)-3 -(2-(3 -methoxyphenethyl)phenoxy)propan-2- yl)oxy)-4-oxobutano ate (S-SARPODEXTM) salt and dextromethorphan (R)-4- ((I- (dimethyl amino)-3- (2- (3 -methoxyphenethyl)phenoxy)prop an-2- yl)oxy)-4-oxobutanoate (R-SARPODEXTM) salt in chloroform or other suitable solvents such as dichloromethane, DMF, etc., which can be separated by crystallization and recrystallization in suitable solvents such DMF and/or chromatographic techniques referred to and described in this specification.
In a multiple stage device, the feed enters a first equilibrium stage and is contacted with an extractant. The two liquid phases are mixed, with droplets of one phase suspended in the second phase, and then the two phases are separated, and DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTM from the first stage is contacted with additional extractant, and the separation process is repeated. The process of (1) contacting DERATINETM, SARPOTINETm, DERADEXTM, DERAPHANTM, or SARPODEXTM with extractant, (2) allowing for equilibrium concentrations to be approached, and (3) separating the liquid phases is repeated until the desired purity of the component of interest is achieved. The number of equilibrium stages will depend on the desired purity, as well as the solubility of the components in the extractant and the flow rates of the feed and extractant.
Mixing the liquids occurs by contacting the feed with the extractant, and the resultant dispersion is settled as the two phases separate. Mixing can occur with the use of baffles or impellers, and the separation process may be carried out in batch fashion or with continuous flow. Settlers can be simple gravity settlers, such as decanters, or can be cyclones or centrifuges, which enhance the rate of settling.
After separation of the phase containing the lower-solubility diastereomer from the phase containing the extractant and the higher-solubility diastereomer, the higher solubility diastereomer may be separated from the extractant by a process such as distillation.
Known liquid-liquid extraction processes that operate on principles that are the same as or similar to those applicable to the separations described herein include the recovery of acetic acid from water using ethyl ether or ethyl acetate as the extractant (Brown, Chem. Engr. Prog.
(1963) 59:65), and the recovery of phenolics from water with methyl isobutyl ketone as the extractant as described by Scheibel in "Liquid-Liquid Extraction" (Perry and Weissburg (eds), Separation and Purification, 3rd Ed. (1978) Chapter 3, John Wiley & Sons, Inc., Hoboken, NJ), incorporated by reference.
Asymmetry, 14, 3716 (2003); incorporated by reference in entirety). The composition of crystalline diastereoisomers is also influenced by the pH of the reaction mixture (Fogassy et al., J. Chem. Res., S 11, 346 (1981); Fogassy et al., J. Chem. Soc. Perkin Trans. 2. (1988), incorporated by reference in entirety). The purity (de) of the diastereoisomer can be improved using a mixture of structurally related resolving agents. It is often referred as "Dutch resolution" in the literature (Kellogg et al., Synthesis, 1626 (2003), incorporated by reference). If the diastereoisomeric salt cannot be separated by fractionated precipitation, it is feasible to get its crystalline solvate by fractionated precipitation from a solvate forming solution (Schindler et al., Chirality, 19, 239 (2007), incorporated by reference). When the solvent, unsuitable for separation of the diastereoisomers, contains structurally partly similar compounds to the solvate forming solution (US 214720, Chem.
Abs. 124, 117097 (1995); U52133894; Chem. Abs. 139, 90595 (2001), incorporated by reference), the separation of enantiomers became feasiable by fractionated precipitation of the diastereoisomeric salt (Palovics et al., Separation of the Mixtures of Chiral Compounds by Crystallization, Advances in Crystallization Processes, pp 1-37 (2012), incorporated by reference).
That eutectic composition can be known from the binary melting point phase diagram. When the initial isomeric composition (ee0) is higher than the eutectic composition, the pure optical isomer cam be crystallized.
Ionic liquids have essentially no vapor pressure, most are air and water stable, and they can either be neutral, acidic or basic.
The properties of an ionic liquid can, however, be tailored by varying the identity of the cation and/or anion. For example, the acidity of an ionic liquid can be adjusted by varying the molar equivalents and type and combinations of Lewis acids used.
Counter ions that may be used include chloroaluminate, bromoaluminate, gallium chloride, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, nitrate, trifluoromethane sulfonate, methylsulfonate, p-toluenesulfonate, hexafluoroantimonate, hexafluoro arsenate, tetrachloroaluminate, tetrabromoaluminate, perchlorate, hydroxide anion, copper dichloride anion, iron trichloride anion, zinc trichloride anion, as well as various lanthanum, potassium, lithium, nickel, cobalt, manganese, and other metal-containing anions.
(Mount Olive, NJ).
Tech. Biotechnol., 68:351-356 (1997); Chem. Ind., 68:249-263 (1996); J. Phys.
Condensed Matter, 5: (supp 34B):B99-B106 (1993); Chemical and Engineering News, Mar. 30, 1998, 32-37; J. Mater.
Chem., 8:2627-2636 (1998); Chem. Rev., 99:2071-2084 (1999); and US
2004/0133058; all of which are incorporated by reference.
Separation can be accomplished using fractionating columns, and preferably under reduced pressure of about 10-3 bar to about 1 bar (US 4874473 A, US 20070225505 Al, incorporated in entirety by reference).
columns, SHISEIDO Chiral CD-Ph, etc. (Fekete et al., Compative Study Separation of Diastereomers by HPLC, Chromatographia, 57, No. 3/4 (2003 February), US
7119211 B2, incorporated in entireity by reference).
ylc_t 04' C0111130101d 1001 Compound 1002 Compound 1003 Compound 1007 1) )o1oIH Ci(OH 0 0 Compound 1008 Compound 50 Compound 51 Compound 52 oft crc( 5) RO
4NHIroo -641 Compound 1009 Compound 1004 Compound 1005 Compound 1006 Compound 1001 1-(dimethylamino)-3- (2-(3 -methoxyphenethyl)phenoxy)propan-2- yl 4-(adamantan-1 -yl amino)-4-oxobutano ate ;
Compound 1002 (S)-1-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy) propan-2-y1 4-(adamantan -1- ylamino) -4- oxobutanoate;
Compound 1003 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-y1 4-(adamantan-1 -yl amino)-4-oxobutano ate ;
Compound 1004 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-y1 4-((3,5-dimethyl adamantan-1-y1) amino) -4- oxo butanoate;
Compound 1005 1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-y1 4-((3,5-dimethyl adamantan- 1 -y1) amino) -4- oxobutano ate;
Compound 1006 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-y1 4-((3,5-dimethyl adamantan-1-y1) amino) -4- oxobutanoate;
Compound 1007 1 -(dimethylamino)-3 -(243 -methoxyphenethyl)phenoxy)prop an-2-yl (2,2,2-trichloro- 1- (dimethoxypho sphoryl)ethyl) succinate;
Compound 1008 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y1 (2,2,2-trichloro- 1- (dimethoxypho sphoryl)ethyl) succinate; and Compound 1008 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y1 (2,2,2-trichloro- 1- (dimethoxypho sphoryl)ethyl) succinate.
PHARMACEUTICAL FORMULATIONS
Subsequently, sodium chloride and sodium saccharin are added to, and uniformly distributed throughout, the paste. Edible coloring and :flavoring materials can be incorporated into the system at any stage of the ipreparative method. In another embodiment, soluble ingredients are added to a compound of Formula I, DERATINETM, SARPOTINETm, SARPODEXTM DERADEXTM, or DERAPHANTM
solution which is prepared in the first step. The paste which is thus obtained can be incorporated readily into a conventional hard candy-forming mass, which mass, in turn, can be worked up, by conventional procedures, into attractive, pleasant-tasting lozenges each containing therapeutically effective quantities of a compound of Formula I, DERATINETM, SARPOTINETm, SARPODEXTM
DERADEXTM, or DERAPHANTM uniformly distributed throughout.
DERADEXTM, or DERAPHANTM and the complex magnesium aluminum silicate and subsequently add a suitable solvent thereto to form a paste therewith. Sodium chloride and sodium saccharin can be added to the dextromethorphan-complex magnesium aluminum silicate mixture prior to forming the mixture into a paste. In the alternative, sodium chloride and sodium saccharin can be added to the paste. Furthermore, suitable flavoring agents and coloring agents can be added either to the dry mixture or to the paste. In carrying out this invention, any medicinally acceptable organic solvent which is suitable for pharmaceutical use and in which a compound of Formula I, DERATINETM, SARPOTINETm, SARPODEXTM DERADEXTM, or DERAPHANTM is soluble can be employed. Thus, for example, organic solvents, such as propylene glycol, glycerine, 1,3-butylene glycol, benzyl alcohol, etc., can be used. In an embodiment of compositions of the invention, benzyl alcohol is employed as the solvent for the saprodexTM.
bentonite; acacia and lower alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of the cellulose ethers).
Exemplary paraben preservatives are Cl -C4alkyl parabens namely methyl, ethyl, propyl, and butyl parabens. In one embodiment, both methyl and propyl paraben are present in the formulation in a ratio of methyl paraben to propyl paraben of from about 2.5:1 to about 7.5:1.
In another embodiment the methyl and propyl paraben ratio is 4:1.
receptor include dizoeilpine 5-methyl -10, 1 1 -dilly dro-5 H-5 1 0-epi minodibenzo [a,d ] [7] amittlene), ketamine (2-(2-chl oropheny1)-2-(methy I amino)cyclohexan- I -one), magnesium, selfotel (QS ,4R
4 -( ph() sphon omethyl )piperidine-2-ca rboxyli c acid), aptigan el ((E)-1-(3-eti iy pheny I )-1-methy1-2-(riaphth ai en- I -yi)gti ani dine), fel b ama te (2 nylpropane- L3-diyi die arbamate), phencyclidine (1-(1-phenyleyclohexyl)piperidine), amantadine (1-aminoadamantine), memantine (3,5 dimethylaminoadamantone), pyrroloquinoline quinone (PQQ, 4,5-dioxo-4,5-dihydro-pyrrolo[2,3-flquinoline-2,7,9-tricarboxylic acid), (R)-(E)-4-(3-phosphonoprop-2- enyl)piperazine-2-carboxylic acid, (R)-2-amino-5- phosphonopentanoate, (S) and (R) 6-(1HTetrazol-5-ylmethyl)decahydroisoquinoline-3-carboxylic acid, (S)- a- amino-5 - (pho sphonomethyl) ,19-bipheny11-3-propanoic acid, (S) and (R) (6)-cis-4-(4-phenylbenzoyl) piperazine-2,3-dicarboxylic acid, c is-4 -phosphonomethy1-2-pipetidine carboxylic acid, 2R,4R,5S-(2 -amino-4 ,5- (1,2-cyclohexyl)-7-phosphonoheptanoic acid), and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, mixtures and pharmaceutically acceptable salts thereof. (US 5,891,885, Christie et al., Native N-Methyl-D-aspartate Receptors Containing NR2A and NR2B Subunits Have Pharmacologically Distinct Competitive Antagonist Binding Sites, The Journal Of Pharmacology And Experimental Therapeutics, Vol. 292, No. 3, pp 1169-74 (2000), incoprated by reference in entirety).
SYNTHESIS OF COMPOUNDS OF THE INVENTION
spectra were obtained on Bruker AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) using residual undeuterated solvent or TMS (tetramethylsilane) as an internal reference.
High-resolution mass spectra (HR-MS) were recorded on a JEOL JMS-700 (JEOL, Tokyo, Japan) using El (electron impact).
Dextrometorphan's specific rotation in water is + 27.6 (20 C, Sodium D-line).
and dextromethorphan positive cation would form hydrogen bond to form a complex and crystallize.
100 ml Carbon tetrachloride. Preparation: Glyceryl tristearate is dissolved in the warm carbon tetrachloride at 55-60 C. A compound of formula I, derivative thereof, SARPODEX TM or derivative thereof is then added and suspended in the solution. The suspension is then spray dried using an inlet temperature of 90 C and an outlet temperature of 40 C. The resulting coated a compound of Formula I, DERATINETm, SARPOTINETm, SARPODEXTM, DERADEXTM, or DERAPHANTM having an average particle size of from about 10 to about 200 microns is then suspended in the following aqueous vehicle.
Ingredients: 10.00 g Tragacanth, USP; 1.20 g Methylparaben, USP; 0.20 g Propylparaben, USP;
0.30 g Saccharin sodium, USP; 3.00 g Sucaryl sodium, USP; 250.00 mL Sorbic acid; 1.00 g Methyl cellulose, 15 cps; 2.00 mL Imitation black currant; and 1000.00 mL
Distilled water.
The organic layer is separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic or 20 optically pure sarpomalonate, respectively depending upon the M1 to yield compounds 38-40.
Racemic sarpomalonate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpomalonate.
Racemic sarpotyrosinate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpotyrosinate.
Racemic sarpotryptophanate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpotryptophanate.
Racemic sarpomaleate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpomaleate.
The organic layer is separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude 25 residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure sarpogrelate, respectively depending upon the M1 to yield compounds 50-52.
Racemic sarpogrelate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpogrelate.
Racemic sarpoglutarate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoglutarate.
Racemic sarpoadipnate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoadipate.
The organic layer is separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure sarpopimelate, respectively depending upon the M1 to yield compounds 59-61.
Racemic sarpopimelate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpopimelate.
Racemic sarposebacate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarposebacate.
Racemic sarpoformate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoformate.
Racemic sarpoacetate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetate.
Racemic sarpopriopionate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpopropionate.
Racemic sarpobutyrate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpobutyrate.
Racemic sarpovalerate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpovalerate.
The organic layer is separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure sarpocaproate, respectively depending upon the M1 to yield compounds 80-82.
25 Racemic sarpocaproate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpocaproate.
Racemic sarpoenanthoate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoenanthoateate.
Racemic sarpocaprylate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpocaprylate.
The organic layer is separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic or 20 optically pure sarpopelargonate, respectively depending upon the M1 to yield compounds 89-91.
Racemic sarpopelargonate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpopelargonate.
Racemic sarpocaprate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpocaprate.
Racemic sarpooxalate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpooxalate.
Racemic sarpoisophthallate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoisophthallate.
The organic layer is separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude 25 residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure sarpoterephthallate, respectively depending upon the M1 to yield compounds 101-103. Racemic sarpoterephthallate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoterephthallate.
Racemic sarposalicilate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarposalicilate.
(5 mL) was added acetylsalicylic acid (0.75 mmol, 1.5 equiv.), triphenylphosphine (0.75 mmol, 1.5 equiv.) and diisopropyl azodicarboxylate (DIAD, 0.75 mmol, 1.5 equiv.) at 0 C. The mixture was stirred at the same temperature for 1 h, and the solvent was removed under reduced pressure. The residue was diluted with Et0Ac (30 mL) and sat. aq. NH4C1 (15 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes:Et0Ac) to obtain compound 107.
Racemic sarpoacetylsalicilate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilates 108 and 109.
aq. NaHCO3 (30 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes:Et0Ac) to obtain compound 107. Racemic sarpoacetylsalicilate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilates 108 and 109.
Then, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL) and washed with H20 (10 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: Et0Ac = 1:2) to afford compound 107 (239 mg, 90% yield). Racemic sarpoacetylsalicilate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilates 108 and 109.
1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y12-acetoxy benzoate (compound 163): colorless oil; Rf = 0.25 (silica gel, hexanes: Et0Ac 1:1); 11-I-NMR
(500 MHz, CDC13): 6 = 7.99 (dd, Ji = 1.6 Hz, J2 = 7.9 Hz, 1H), 7.53-7.50 (m, 1H), 7.18 (ddd, Ji = 1.1 Hz, J2 = 7.9 Hz, J3 = 7.9 Hz, 1H), 7.18-7.14 (m, 2H), 7.10-7.06 (m, 2H), 6.89-6.86(m, 2H), 6.77 (d, J = 7.7 Hz, 1H), 6.72-6.71 (m, 2H), 5.56-5.51 (m, 1H), 4.28-4.22(m, 2H), 3.75 (s, 3H), 2.92-2.71 (m, 6H), 2.32 (s, 6H), 2.30 (s, 3H) ppm; '3C-NMR
(125 MHz, CDC13): 6 = 169.7, 163.9, 159.7, 156.5, 150.9, 144.1, 134.0, 131.9, 130.5, 130.3, 129.3, 127.4, 126.1, 123.9, 123.4, 121.0, 120.9, 114.2, 111.39, 111.37, 71.2, 67.6, 59.4, 55.2, 46.4, 36.5, 32.8, 21.1 ppm; HRMS (El): calcd for C29H33N06 lMI: 491.2308, found 491.2310.
7.8 Hz, 1H), 7.11 (dd, Ji = 1.7 Hz, J2 = 7.4 Hz, 1H), 6.87 (ddd, Ji = 1.0 Hz, J2 = 7.4 Hz, J3 =
7.4 Hz, 1H), 6.84 (t, J= 8.9 Hz, 2H), 6.78 (t, J= 1.9 Hz, 1H), 6.76-6.73 (m, 1H), 5.39-5.34 (m, 1H), 4.19-4.09 (m, 2H), 3.80 (s, 3H), 2.91-2.84 (m, 4H), 2.69-2.61 (m, 2H), 2.30 (s, 6H), 2.05 (s, 3H) ppm; 13C-NMR (125 MHz, CDC13): 6 = 170.8, 159.7, 156.5, 144.2, 130.5, 130.3, 129.4, 127.4, 121.0, 120.9, 114.3, 111.3, 111.2, 70.4, 67.7, 59.7, 55.3, 46.4, 36.6, 33.2, 21.4 ppm; HRMS (E1): calcd for C22H29N04 lMI: 371.2097, found 371.2095.
1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y1-2-hydroxy benzoate (compound 165) colorless oil; Rf = 0.23 (silica gel, hexanes:Et0Ac 2:1); 1H-NMR (500 MHz, CDC13): 6 = 10.69 (s, 1H), 7.83 (dd, Ji = 1.7 Hz, J2 = 8.0 Hz, 1H), 7.44-7.41 (m, 1H), 7.20-7.16 (m, 2H), 7.11 (dd, Ji = 1.6 Hz, J2 = 7.4 Hz, 1H), 6.96 (dd, Ji = 0.9 Hz, J2 = 8.4 Hz, 1H), 6.91-6.88 (m, 2H), 6.81-6.77 (m, 1H), 6.76-6.72 (m, 3H), 5.70-5.66 (m, 1H), 4.30-4.29 (m, 2H), 3.76 (s, 3H), 2.91-2.82 (m, 6H), 2.40 (s, 6H) ppm; 13C-NMR (125 MHz, CDC13): 6 =
169.6, 161.8, 159.7, 156.3, 144.0, 136.0, 130.5, 130.4, 130.1, 129.4, 127.4, 121.2, 120.9, 119.4, 117.8, 114.3, 112.5, 111.3, 111.2, 71.2, 67.6, 59.4, 55.2, 46.1, 36.5, 32.8 ppm; HRMS (E1):
calcd for C27f131N05 [M-1: 449.2202, found 449.2200.
7.8 Hz, J3 = 7.8 Hz, 1H), 7.28 (ddd, Ji = 1.1 Hz, J2 = 7.7 Hz, J3 = 7.7 Hz, 1H), 7.21-7.17 (m, 2H), 7.13 (dd, Ji = 1.5 Hz, J2 = 7.4 Hz, 1H), 7.11 (dd, Ji = 1.0 Hz, J2 = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.81 (d, J= 7.7 Hz, 1H), 6.75-6.73 (m, 2H), 4.62-4.53 (m, 2H), 4.20-4.12 (m, 2H), 3.77 (s, 3H), 3.29-3.24 (m, 1H), 2.95-2.85 (m, 4H), 2.51 (s, 6H), 2.31 (s, 3H) ppm; 13C-NMR
(125 MHz, CDC13): 6 = 169.9, 164.3, 159.7, 156.5, 150.9, 144.0, 134.1, 131.7, 130.4, 130.3, 129.4, 127.4, 126.1, 124.0, 123.2, 121.0, 120.9, 114.2, 111.4, 111.1, 65.7, 62.8, 62.0, 55.2, 42.6, 36.6, 32.6, 21.1 ppm; HRMS (E1): calcd for C29H33N06 lMI: 491.2308, found 491.2309.
of 100 mM
pH=7 deuterated phosphate-buffered saline (D-PBS) diluted with 9.00 mL D20 to a final concentration of 25 mM. 100 mM D-PBS pH=7 (pH paper) buffer is prepared by dissolving 259.5 mg of K3PQ4 in D20 (12.00 mL) and adding 264 pL 20% DC1 in D20. The reaction mixture is shaken at room temperature for 11 days while monitoring for completion of hydrogen/deuterium (HID) exchange by LC/MS.
of total volume) is diluted with 40 mL saturated NaHCO3 and extracted once with Et0Ac (200 mL). The organic layer is quickly dried over Na2SO4. Evaporation of the solvent gives the compound which is stored in a freezer.
HYDROCHLORIDE: 1-dimethylamino-3-12-12-(3-methoxyphenyl)ethyllphenoxyl-2-propanol hydrochloride A 250 ml 13.7 g and water 25 ml were taken in a single-neck flask and stirred to dissolve. The solution is treated with 20% aqueous sodium hydroxide to a pH
about 9 to about 14, and was extracted with 30 ml of toluene, and the organic layer was concentrated at 50 C under reduced pressure to give a brown oil, which was dissolved in 30 mL of tetrahydrofuran. Then, butyryl anhydride 4.5 g was added and heated to reflux with stirring for about 1 to about 4 hours, and concentrated to dryness under reduced pressure at 40 C. Ethyl acetate (25 mL) is added to dissolve the residue and saturated hydrogen chloride in ethyl acetate solution is added dropwise to adjust PH 1 or lower while stirring for about 50-60 mm to obtain sarpogrelate hydrochloride crude wet product, and dried under reduced pressure (-0.08-0.1MPa) at 45 to 55 C to yield crude sarpogrelate hydrochloride 14.7 g, yield 86%, HPLC purity 98.6 %.
SARPOGRELATE: The crude sarpogrelate hydrochloride 5g was dissolved in butanone (20 mL), heated while stirring until dissolved, refluxed for 20-30 mm, cooled to 25-35 C, continued stirring 40-60 mm, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55-65 C and dried under reduced pressure to 24 h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9%.
SARPOGRELATE: The crude sarpogrelate hydrochloride 5g in butanone 30m1 was heated with stirring until dissolved and refluxed 20-30min, cooling to 25-35 C, incubated with stirring 40-60 mm, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55-65 C and dried under reduced pressure to 24 h, to give 4.55 sarpogrelate hydrochloride, yield 91 %, HPLC purity 99.7%.
SARPOGRELATE: The crude sarpogrelate hydrochloride 5 g in butanone 40m1 is heated with stirring until dissolved and refluxed 20-30 min, cooling to 25--35 C, incubated with stirring 40-60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white solid, 55-65 C and dried under reduced pressure to 24 h, to give sarpogrelate hydrochloride 4.5 g, yield 90%, HPLC purity 99.8 %.
SARPOGRELATE: The crude product was sarpogrelate hydrochloride 5 g, join butanone 20 ml, heated with stirring until dissolved and refluxed 20-30 mm, cooled slowly with stirring to room temperature, at -10 C stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55-65 C and dried under reduced pressure to 24 h, to give the hydrochloride sarpogrelate 4.62 g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.
HYDROCHLORIDE ((-)-4-((1-(dimethylamino)-3-(2-(3-ethoxyphenethyl) phenoxy)propan-2-yloxy) -4-oxobutanoic acid hydrochloride): Sarpogrelate hydrochloride was separated with the XBridge0 C18 3.5pm, 2.1x50 mm column, using a mobile phase: gradient elution from 10%
MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA, with a flow rate of 0.5 ml/min, at nm, to yield 5.30 mg of enantiomer (99% HPLC purity). NMR: 400 MHz 1H-NMR
(C0300, ppm) 7.20-7.14 (m, 2H) 7.11 (dd, J=7.4, 1.6 Hz, 1H) 6.94-6.87 (m, 2H) 6.79-6.71 (m, 3H) 5.70-5.62 (m, 1 H) 4.18 (dd, J=10.6, 4.1 Hz, 1 H) 4.15 (dd, J=10.6, 4.7 Hz, 1H) 3.75 (S, 3H) 3.70 (dd, J=13.8, 10.1Hz, 1H) 3.54 (dd, J=13.8, 2.3 Hz, 1H) 2.98 (s, 6H) 2.96-2.77 (m, 4H) 2.76-2.53 (m, 4H). ESI-MS, m/z): 429 11\4+H1+. Melting point ( C): 155-156. Optical rotation, alpha [Di: -20.0 (c 0.33, Me0H).
A COMPOUND SELECTED FROM FORMULA I COMPOUNDS COMPRISING FDIc AND FDId (COMPOUNDS 219-269): Dissolve the free base (FDIc or FDId) (0.25 mole) and dextromethorphan (0.25 mole) in 20 ml of acetone, add the solution to a solution of a di or tri acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry. The di and tri acids include, but not limited to adipic acid, aspartic acid, N-acyl aspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acyl glutamic acid, glucaric acid (saccharic acid), malic acid, maleic acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthallic acid, isophthallic acid, terephthallic acid, rhamnonic acid, sebacic acid, succinic acid, and tartaric acid. Thus, forming addition salts such as:
Ladanyi L et al., Stereochemistry and enantiomeric purity of a novel anxiolytic agent, deramciclane fumarate.
Chirality 11:689-93 (1999), incorporated by reference). Fumarate of compound 829 can be prepared by a three-step synthesis scheme using readily available and low-cost starting materials (camphor) with very high enantiomeric purity (>99.9%). 3.9 g (0.1 g atom) of potassium metal are added to 100 ml of anhydrous xylene, and the mixture is reacted with 23.04 g (0.1 mole) of(-0-2-pheny1-1,7,7-trimethyl-bicy- clo(2,2,1)heptan-2-ol under vigorous stirring.
When the formation of hydrogen gas has ceased, a solution of 10.3 g (0.11 moles) of 1-dimethylarnino-2-chloro-eththe in ml of anhydrous xylene is introduced, under further stirring. The reaction mixture is kept at 100 C. for 6 hours, then washed thrice with 50 ml of water, and extracted with a solution of 15 g (0.1 mole) of tartaric acid in 80 nil of water or with 0.11 mole of diluted aqueous hydrochloric 25 acid. The aqueous phase is made alkaline to pH 10 with an aqueous solution of potassium hydroxide of 20% under cooling (at 0 to 5 C). The base separated as an oil is extracted with ether.
After distilling off the solvent the residue is either .purified with fractionated distillation under vacuo or used for salt formation. Yield: 25.2 g (D.6%) of a pale yellow oil, BP: 1310-1350 C./26.7 Pa, Hydrogen fumarate, m.p.: 180 -1820 C.The enantiomeric separation is accomplished by HPLC
30 on Chiralcel OD (250 x 4.6 mm; 10 nm) and hexane-ethanol (99.5:0.5) as mobile phase at room temperature. Chemical Formula: C24H35N05. Molecular Weight: 417.55. Elemental Analysis:
Calculated: C: 69.03%, H: 8.45%, N: 3.35%, Found: C: 69.05%, H: 8.59%, N:
3.44%;
Deramciclane is at least 10-fold selective against dopamine D2 receptors (Gacsalyi I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models.
Drug Dev Res (1997) 40:333-348). Extensive evaluation of Compound 829 in dopaminergic models has not revealed any functional significance of these receptor binding data. Compound 829 was not found to elevate prolactin ¨ at least within the dose-range that covers therapeutically relevant exposures (Laine K
et al., Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone. Eur J Clin Pharmacol (2003) 59: 761-766).
Psychopharmacology (1998) 136:99-104) and humans (Kanerva H et al., Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration--a positron emission tomography study. Psychopharmacology (1999) 145:76-81).
receptor ligands.
ScientificWorldJournal. 2010 Sep 14;10:1870-85; Meltzer HY et al., Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia.
Curr Pharm Biotechnol. 2012 Jun;13(8):1572-86).
208), both deramciclane 30 mg/day and 60 mg/day doses provided clinically relevant improvements in Hamilton Anxiety Rating scale HAM-A total score after 8 weeks of treatment, reaching statistical significance compared with placebo (n=51) in the 60 mg/day dose group (p =
0.024, n=54) and a clear trend in the 30 mg/day group (p = 0.059, n=53), but not in the 10 mg/day group (n=54). On the HAM-A psychic anxiety factor, significant improvements were seen in patients in the deramciclane 30 mg/day and 60 mg/day treatment groups compared with those in the placebo group.
Eur J Clin Pharmacol (2004) 59:893-898, incorporated by reference).
C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; m/z: 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); Elemental Analysis: C, 72.57; H, 8.24; N, 4.98; 0, 14.21; Boiling Point: 1300.87 [K]; Melting Point: 890.75 [K];
Critical Temp: 1176.29 [K]; Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy:
126.8 [kJ/moll; Log P: 5.06; MR: 160.74 [cm3/mol]; Henry's Law: 16.03; Heat of Form: -719.51 [kJ/moll; tPSA: 77.1;
CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.
C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; m/z: 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); Elemental Analysis: C, 72.57; H, 8.24; N, 4.98; 0, 14.21; Boiling Point: 1300.87 [K]; Melting Point: 890.75 [K];
Critical Temp: 1176.29 RC]; Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy:
126.8 [kJ/moll; Log P: 5.06; MR: 160.74 [cm3/mol]; Henry's Law: 16.03; Heat of Form: -719.51 [LI/mol]l tPSA: 77.1;
CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.
C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; m/z: 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); Elemental Analysis: C, 72.57; H, 8.24; N, 4.98; 0, 14.21; Boiling Point: 1300.87 [K]; Melting Point: 890.75 [K];
Critical Temp: 1176.29 [K];Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy:
126.8 [kJ/moll; Log P: 5.06; MR: 160.74 [cm3/mol]; Henry's Law: 16.03; Heat of Form: -719.51 [LI/mol]l tPSA: 77.1;
CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.
1191.88 [K]; Critical Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66 [kJ/moll; Log P: 6; MR:
169.53 [cm3/mol]; Henry's Law: 15.78; Heat of Form: -730.31 [kJ/moll; tPSA:
77.1; CLogP:
7.5534; CMR: 17.0669; LogS: -7.773; pKa: 8.362.
Chemical Formula: C36H50N205; Exact Mass: 590.37; Molecular Weight: 590.81; m/z: 590.37 (100.0%), 591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); Elemental Analysis: C, 73.19; H, 8.53; N, 4.74; 0, 13.54; Boiling Point: 1347.11 [K]; Melting Point: 961.09 [K]; Critical Temp:
1191.88 [K]; Critical Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66 [kJ/moll; Log P: 6; MR:
169.53 [cm3/mol]; Henry's Law: 15.78; Heat of Form: -730.31 [kJ/moll; tPSA:
77.1; CLogP:
7.5534; CMR: 17.0669; LogS: -7.773; pKa: 8.362.
Chemical Formula: C36H50N205; Exact Mass: 590.37; Molecular Weight: 590.81; m/z: 590.37 (100.0%), 591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); Elemental Analysis: C, 73.19; H, 8.53; N, 4.74; 0, 13.54; Boiling Point: 1347.11 [K]; Melting Point: 961.09 [K]; Critical Temp:
1191.88 [K]; Critical Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66 [kJ/moll; Log P: 6; MR:
169.53 lcm3/moll; Henry's Law: 15.78; Heat of Form: -730.31 11(J/moll; tPSA:
77.1; CLogP:
7.5534; CMR: 17.0669; LogS: -7.773; pKa: 8.362
Chemical Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z:
667.13 (100.0%), 669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%), 671.13 (4.2%), 673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%), 673.13 (1.4%); Elemental Analysis: C, 50.28; H, 5.58; Cl, 15.90; N, 2.09; 0, 21.53; P, 4.63
Chemical Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z:
667.13 (100.0%), 669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%), 671.13 (4.2%), 673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%), 673.13 (1.4%); Elemental Analysis: C, 50.28; H, 5.58; Cl, 15.90; N, 2.09; 0, 21.53; P, 4.63
Chemical Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z:
667.13 (100.0%), 669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%), 671.13 (4.2%), 673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%), 673.13 (1.4%); Elemental Analysis: C, 50.28; H, 5.58; Cl, 15.90; N, 2.09; 0, 21.53; P, 4.63.
BIOLOGICAL STUDIES
exemplified by 4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4-oxobutanoic acid (represented by compounds 50, 51, and 52); 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ol (represented by compounds 146, 147, 148);
OIN
0, 0 N¨
H
Compound 146 Compound 147 Compound 148 Compound Racemate M1 Enantiomer 1 (MI-El) Enantiomer 2 (M1L-E2) Enantiomer 1-(dimethylamino) 3 (2 (3 (S)-1-(dimethylamino)-3-(2-(3-(R)-1-(dimethylamino)-3-(2-(3- N,N-dimethy1-2-(41 R,2S,4R)-1,7,7-methoxyphenethypphenoxy) methoxyphenethyl)phenoxy) methoxyphenethyl)phenoxy) trimethy1-2-phenylbicyclo [2.2 . 1]
propan-2-ol propan-2-ol propan-2-ol heptan-2-yl)oxy)ethan-1-amine 4411)v. 0"--'inr)LOH
OH
Compound 50 Compound 51 Compound 52 Sarpogrelate Racemate (SQL) Sarpogrelate Enantiomer 1 (SGL-E1) Sarpogrelate Enantiomer 2 (SGL-E2) 4-((1-(dimethylamino) 3 (2 (3 (S)-44( 1 -(dimethylamino)-3-(2-(3- (R)-4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propa methoxyphenethyl)phenoxy)propan- methoxyphenethyl)phenoxy)propan-2-n-2-yl)oxy)-4-oxobutanoic acid 2-yl)oxy)-4-oxobutanoic acid yl)oxy)-4-oxobutanoic acid N,N-ditnethy1-2-[RIR,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]
heptanyl] my] ethanamine or N,N-dimethy1-24(1R,2S,4S)-1,7,7-trimethy1-2-phenylbicyclo [2.2.1]heptan-2-yeoxy)ethan-1-amine (Compound 829, 5 deramciclane) and compounds of Formula II, exemplified by dextromethorphan, derivatives and metabolites thereof.
RECEPTOR BLOCKADE: Antipsychotic drugs attenuate locomotor hyperactivity induced by psychostimulant and psychotomimetic drugs in laboratory rodents. While hyperactivity induced 10 by dopaminergic agents such as d-amphetamine is reversed by both typical and atypical antipsychotics that are currently in the clinic use, 5HT2A receptor antagonists are more effective against hyperactivity induced by NMDA receptor antagonists such as phencyclidine-like channel blockers (Carlsson et al., The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice, J. Neural.
15 Transm. 106(2):123-9 (1999)). Pimavanserin (ACP-103) is an example of a 5HT2A receptor antagonist that was administered in mice in combination with 0.3 mg/kg MK-801 (i.p.) 15 min before the test session (Vanover et al., Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N- (1-methylpiperidin-4-y1) -N'- (4-(2- methylpropyloxy) phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine (2A) 20 receptor inverse agonist, J Pharmacol Exp Ther. 317(2):910-8 (2006 May);
incorporated by reference). Motor activity data were collected during a is -mm session in a lit room. Mice had no prior exposure to the motor cages. Immediately before placing the mice in the locomotor chambers, effects on myorelaxation/ ataxia were determined by placing each of the mouse's forepaws in contact with a horizontal wire while holding the mouse by the base of the tail. Mice were required to bring at least one hindpaw in contact with the wire within 10 s to be scored as a "pass" and failure to do so was considered ataxic. Each dose or dose combination was tested in a separate group of mice. ACP-103 significantly attenuated MK-801-induced hyperactivity in mice at doses of 0.1 and 0.3 mg/kg s.c. [F(7,63)=6.010; p<0.00011, consistent with an antipsychotic-like effect.
incorporated by reference in its entirety), dextromethorphan is used at the dose of 10 mg that may be administered twice a day. Currently known clinical dose of Sarpogrelate is 100 mg that is typically given three times a day (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-874; incorporated by reference in its entirety).
Thus, current clinical dose of Sarpogrelate significantly exceeds that of dextromethorphan. Given that the molecular weight of sarpogrelate is about 429 and molecular weight of dextromethorphan is about 271, combined use of dextromethorphan and sarpogrelate at the current clinical doses does not result in a molar ratio of 1:1. However, such molar ratio of 1:1 is a pre-requisite for preparing and using sarpogrelate salts of dextromethorphan. As the current clinical use of sarpogrelate is for peripheral (non-CNS) indications (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-874;
incorporated by reference in its entirety), use of sarpogrelate for CNS indications may require lower doses and therefore enable co-administration with dextromethorphan as sarpogrelate salt of dextromethorphan or as a mixture in a molar ratio of 1:1. In laboratory animals, sarpogrelate is typically given at doses of 25 mg/kg and above to induce peripheral effects (Ma et al., Effective treatment with combination of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine 2 receptor antagonist on glucocorticoid-induced whole-body insulin resistance with hyperglycemia. J
Diabetes Investig 7(6):833-844 (2016); incorporated by reference in its entirety). An example of higher CNS activity of sarpogrelate is provided by an example where sarpogrelate is given to Sprague-Dawley rats at the doses of 0.3, 1 and 3 mg/kg 30 mm prior to a centrally acting 5-HT2A
agonist DOI (3 mg/kg;
(1(2,5-dimethoxy-4-iodopheny1)-2-aminopropane)hydrochloride) and frequency of DOI-induced head shakes is reduced by co-administration of a compound of Formula I, SARPODEXTM, DERADEXTM, or DERAPHANTM.
receptor (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta0) clinical use. Pharmacol Ther. 164:170-82 (2016 August); incorporated by reference in its entirety).
However, DEX is a less potent NMDA receptor antagonist than its metabolite, DO. Accordingly, DEX is less likely to induce phencyclidine-like motor activity than DO. The behavioral effects of DEX, DO and phencyclidine (PCP) were compared in rats. DO (15-120 mg/kg) was similar to PCP
(1.25-20 mg/kg) in inducing dose-dependent locomotor hyperactivity, stereotypy and ataxia. DEX
(15-120 mg/kg) induced moderate hyperactivity only at the higher doses about 45 mm after treatment. DEX and DO modified the locomotor facilitation induced by 10 mg/kg PCP in opposite directions. Pretreatment with DO facilitated, whereas DEX dose-dependently inhibited PCP-elicited hyperactivity (Szekely et al., Induction of phencyclidine-like behavior in rats by DO but not DEX, Pharmacol Biochem Behav, 40(2):381-6 (1991 October); incorporated by reference in its entirety).
prevents emergence of hyperactivity in DEX -treated subjects. These studies are paralleled by measurements plasma DEX levels. The combination of pharmacokinetic (plasma DEX concentration) and pharmacodynamic (MK-801- and DEX -induced hyperactivity) studies are used to identify the M1 enantiomer and the dose level(s) producing the most optimal ratio of anti-hyperactivity and DEX
metabolism-suppressing effects.
incorporated by reference in its entirety). More specifically, application of DEX via drinking water (4 mg/mi) overnight changed neither basal plasma insulin nor fasting blood glucose concentrations in mice, but led to significantly higher glucose-induced plasma insulin concentrations and glucose tolerance than were seen in non-DEX-treated controls (glucose administered intraperitoneally at 1.5 mg/kg body weight).
demonstrated that glucose-stimulated insulin secretion and glucose tolerance are not observed in mice genetically engineered to lack NMDA receptor function.
dosages resulted in significantly (P < 0.05) higher maximal serum insulin concentrations compared to those seen with placebo.
(glucose AUC1-3 h) was significantly (P < 0.05) smaller in individuals who received 270 mg doses of DEX than in the same individuals receiving placebo on a different treatment day.
receptors (Yamada et al., Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in rats: involvement of the peripheral 5-HT2A receptor. Eur J Pharmaco1.323(2-3):235-40 (1997);
incorporated by reference in its entirety). More specifically, administration of non-selective 5HT receptor agonist such as 5-methoxytryptamine induced hyperglycemia that is prevented by pretreatment with 5-HT2A receptor antagonist ketanserin as well as peripherally acting 5-HT2 receptor antagonist, xylamidine. These results suggested that 5-methoxytryptamine-induced hyperglycemia is mediated by the peripheral 5-HT2A receptors.
Though this has been largely attributed to weight gain, there is also a direct, receptor-mediated effect of antipsychotics on glucose tolerance. Certain 5HT2A receptor antagonists such as ketanserin impair insulin sensitivity (Gilles et al., Antagonism of the serotonin (5-HT)-2 receptor and insulin sensitivity: implications for atypical antipsychotics. Psychosom Med. 67(5):748-51 (2005)); incorporated by reference in its entirety). In the study by Gilles et al., ten healthy male volunteers were included in a double-blind, placebo-controlled crossover study of a single dose of 40 mg of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by means of the euglycemic-hyperinsulinemic clamp technique. Subjects were treated with the alpha-1 adrenergic antagonist phenoxybenzamine in both parts of the study to control for ketanserin's effects at the level of this receptor. Compared with the placebo condition, subjects showed a significantly decreased insulin sensitivity after ketanserin (placebo: 9.4 +/-3.6 mg/kg/min;
ketanserin: 7.7 +/- 2.1 mg/kg/min; p = .047).
and DO are NMDA receptor channel blockers, and NMDA receptor inhibition in pancreatic islets was suggested to be responsible for glucose-stimulated insulin secretion, and glucose intolerance enhanced by DEX and DO (Marquard et al., Characterization of pancreatic NMDA
receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015);
incorporated by reference in its entirety). Since DO is more potent NMDA receptor channel blocker than DEX
(Pechnick et al., Comparison of the Effects of DEX, DO, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis, The Journal Of Pharmacology and Experimental Therapeutics, 309:515-522 (2004); incorporated by reference in its entirety), inhibition of DEX
metabolism via CYP2D6 may reduce the expression of effects of DEX on glucose-stimulated insulin secretion and glucose tolerance and, therefore, risks of metabolic side-effects.
Accordingly, a 5HT2A
receptor inverse agonist or antagonist is chosen to produce therapeutically relevant central 5HT2A
receptor occupancy at the doses that are at lowest risk of producing unwanted metabolic effects such as, but not limited to, glucose intolerance.
incorporated by reference in its entirety). In these studies, Otsuka Long-Evans Tokushima Fatty rats, a model of type 2 diabetes, were randomly assigned to 2 groups; those with 30 mg/kg BW/d a compound of Formula I treatment of 4 weeks (HTB group) and without (control group). The glucose infusion rate was significantly increased in the HTB group compared with the control group. The blood glucose levels after oral glucose tolerance test and levels of plasma insulin and lipids were significantly lower in the HTB group than in the control group. a compound of Formula I was shown to reverse insulin resistance induced by various means including glucocorticoid drug treatment (Ma et al., Effective treatment with a combination of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine-2 receptor antagonist on glucocorticoid-induced whole-body insulin resistance with hyperglycemia J Diabetes Investig 7: 833-844 (2016);
incorporated by reference in its entirety).
34(1-2):18-30 (2009); incorporated by reference in its entirety).
receptor antagonist, in patients with peripheral arterial disease. Circ J
70(11):1451-6 (2006);
incorporated by reference in its entirety). Indices of insulin resistance (fasting immunoreactive insulin) were measured before and after 2 weeks of a compound of Formula I
administration (300 mg/day) in 24 patients (19 men, 76+/-9 years) with peripheral arterial disease. Sixteen of the 24 patients were also examined after 3 months of treatment. After 2 weeks of treatment, significant decreases in fasting immunoreactive insulin (p=0.03) were observed. After 3 months of treatment, significant decreases in fasting immunoreactive insulin (16.0+/-10.3 vs 9.2+/-2.0 microU/ml, p=0.03) were maintained.
receptor antagonist and 2D6 inhibitory properties. Both enantiomers of metabolite are biologically active and share the ability to block 5HT2A receptors and 2D6. To establish which of the enantiomers has the most optimal properties for being combined with DEX, effects of these substances alone and in combination with DEX on oral glucose tolerance are assessed (Taniguchi et al., Diabetes, 55, 2371-2378 (2006); incorporated by reference in its entirety). This method is based on the measurement of whole blood glucose and plasma insulin. Test substances are administered to male Sprague-Dawley rats (group size: 8 per group). Animals are tested after an overnight food deprivation and individually housed. Test substance is administered 60 minutes before glucose challenge, i.e. after baseline blood glucose measurement.
Animals are challenged with glucose at 2 g/kg as an oral gavage at TO, after blood glucose measurement. Blood glucose is measured from a drop of blood collected from the cut tip of the tail, using a commercially available glucose-meter at 8 time-points: baseline (before treatment), TO (before glucose) and then 15, 30, 60, 90, 120 and 180 minutes post-glucose challenge.
PATHOPHYSIOLOGY: Links between a chronic diabetic metabolic situation and the risk and emergence of AD pathophysiology have long been suspected and substantiated in the recent years (Goldwasser et al., Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link between Diabetes Mellitus and Alzheimer's Disease. J Alzheimers Dis 54(2):445-56 (2016 Aug 1); incorporated by reference in its entirety). In several large post-mortem series, more than a third of all subjects clinically diagnosed with typical AD showed evidence of cerebrovascular disease and had to be re-classified as mixed dementia (Grandal Leiros et al., Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in a psychogeriatric clinic, Neurologia S0213-4853(16)30070-6 (2016); incorporated by reference in its entirety). From a clinical perspective, it is desirable to extend AD therapy beyond currently approved drugs and mechanisms, and also address the cognitive impairment by optimizing a latent diabetic metabolic situation or the fairly frequent Type 2 diabetes in the elderly subjects.
Indeed, glycaemic control is thought to have an impact o the severity of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep, 16 (9):87 (2016); incorporated by reference in its entirety).
described above, it is, therefore, conceivable to attempt an added benefit on both, symptoms and disease progression in AD, and in cognitive impairment of mainly vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment, etc.).
Immediately before placing the mice in the locomotor chambers, effects on myorelaxation/ataxia were determined by placing each of the mouse's forepaws in contact with a horizontal wire while holding the mouse by the base of the tail. Mice were required to bring at least one hindpaw in contact with the wire within 10 s to be scored as a "pass" and failure to do so was considered ataxic.
Each dose or dose combination was tested in a separate group of mice. ACP-103 significantly attenuated MK-801-induced hyperactivity in mice at doses of 0.1 and 0.3 mg/kg s.c.
lF(7,63)=6.010; p<0.00011, consistent with an antipsychotic-like effect.
receptors with the Ki values that are approximately one order of magnitude higher than those of sarpogrelate enantiomers (Table 1). There are no meaningful differences between enantiomers in terms of 5-HT2A receptor binding for sarpogrelate or its main metabolite.
Analysis of variance (ANOVA) has revealed main effects of the M1 dose and the interaction between M1 dose and MK-801 treatment factors for the (-) M1 enantiomer [F(2,39)=6.154;
p=0.0048, F(2,39)=4.613; p=0.0159, respectively] and not for the (+) M1 enantiomer [F(2,42)=0.5211;
p=0.5977, F(2,42)=0.5229; p=0.5966, respectively]. As shown in Figure 7, both doses of the (-)M1 enantiomer as well as 3 mg/kg of a prototypical 5-HT2A receptor antagonist M-100,907 reduced hyperactivity induced by MK-801 (Dunnett' s multiple comparisons test). Thus, despite no significant differences between M1 enantiomers in terms of binding to 5-HT2A receptors, surprisingly, only one of the enantiomers exerts efficacy in a preclinical model of psychomotor activation that is known to be sensitive to 5-HT2A receptor blockade.
OLFACTORY BULBECTOMY IN RATS: In a dedicated set of studies, adult male Sprague-Dawley rats (Charles River, Germany) were subjected to bilateral olfactory bulbectomy performed under ketamine/xylasine anesthesia. The animals were allowed to recover for 14 days following surgery while being handled daily to eliminate any aggressiveness that would otherwise arise.
Sham-operated animals were treated in the same way but the olfactory bulbs were left intact. Drugs administration and locomotor activity testing were performed 4 times for each rat with 72 hours break between consecutive test sessions. Prior to each test session, animals were first treated with dextromethorphan (0, 15, 30 or 60 mg/kg. per os) followed 15 mm later by sarpogrelate (1, 3 and 10 mg/kg, intraperitoneal) and another 15 mm later were placed into Opto-Varimex cages for locomotor activity recording over 30 mM. Hyperactivity in rats after olfactory bulbectomy is observed mostly during the early portion of the test sessions. Figure 8 presents average activity counted over the first 15 mM of the test when activity of the bulbectomized animals was significantly higher than that of the sham controls. ANOVA revealed a significant main effects of both surgery and sarpogrelate dose factors [F(1,88)=5.04, p=0.0273;
F(3,88)=5.02, p=0.0029, respectively]. Post hoc pairwise comparisons (Sidak's multiple comparisons test) confirmed that significant differences between bulbectomized and sham-operated were observed only in rats that were pretreated prior to the test with vehicle instead of sarpogrelate.
Bulbectomized rats pretreated with 3 or 10 mg/kg of sarpogrelate spent less time in ambulations compared with the respective controls that received vehicle instead of sarpogrelate. These anti-hyperactivity effects of sarpogrelate are observed at the doses that do not affect activity of sham-operated rats and therefore do not reflect a generalized non-specific impairment of motor capabilities.
Thus, surprisingly, despite being previously referred to as a peripherally restricted 5-HT2A
receptor antagonist with only minimal penetration across the blood-brain barrier (Obata H et al.
Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral. Eur J
Pharmacol 404(1-2):95-102 (2000)), sarpogrelate is observed to exert behaviorally specific anti-hyperactivity effects in rats after olfactory bulbectomy, a model commonly used to study CNS drugs such as antidepressants.
VITRO AND IN VIVO: Dextromethorphan 0-demethylase activity was determined in human liver microsomes. Sarpogrelate (1.0E-8 M to 3.0E-5 M) or M-1 (concentration:
3.0E-9 M to 1.0E-5 M) and dextromethorphan were dissolved in acetonitrile and serially diluted with acetonitrile to the required concentrations to give a final organic solvent concentration of 1.0% in the incubation mixture. The incubation mixtures contained pooled human liver microsomes (final concentrations:
0.25 mg/mi), dextromethorphan, and a NADPH-generating system (1.3 mM NADP+, 3.3 mM
glucose 6-phosphate, 3.3 mM MgCl2, and 0.4 U/ml glucose-6-phosphate dehydrogenase). After incubation and centrifugation, the supernatant was diluted 100-fold with acetonitrile and then injected into the LC-MS/MS system. All incubations were performed in triplicate, and mean values were used for analysis. The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting. Both sarpogrelate enantiomers inhibited CYP2D6-mediated dextromethorphan 0-demethylation (Table 4).
Compound IC50, uM
50 1.2 (-i-)51 0.58 (-) 52 1.3 (+) 147 0.038 (-) 148 0.096
Based on previous in vivo studies, sarpogrelate was classified as a weak 2D6 inhibitor. This classification was based on a less than 2-fold increase in the substrate AUC
(i.e. per guidance provided by the US Food and Drug Administration, Draft guidance for industry:
drug interaction studies ¨ study design, data analysis, implication for dosing and labeling recommendations. Center for Drug Evaluation and Research, US FDA
(2012), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/uc m292362.pdf).
Apparent terminal elimination half-life was estimated at 1.21 0.159 h.
Formation of M1 metabolite of sarpogrelate was rapid as the highest M1 concentrations were measured at the first sampling time points. In spite of the rapid formation, concentrations of the free M1 metabolite were orders of magnitude lower in the circulation than those of the parent compound (Ml/sarpogrelate ratio of 2.98 0.597 %). Thus, although M1 enantiomers are significantly more potent 2D6 inhibitors than the parent compound, potential impact of M1 is mitigated by low relative exposure to M1 suggested by the ratio of plasma AUC for M1 and sarpogrelate.
and stored at this temperature until processed for LC-MS analysis.
PHENCYCLIDINE-INDUCED
HYPERACTIVITY IN RATS TREATED BY A COMBINATION OF SARPOGRELATE
AND DEXTROMETHORPHAN: The behavioral effects of DEX, DO and phencyclidine (PCP) were compared in rats. DO (15-120 mg/kg) was similar to PCP (1.25-20 mg/kg) in inducing dose-dependent locomotor hyperactivity, stereotypy and ataxia. DEX (15-120 mg/kg) induced moderate hyperactivity only at the higher doses about 45 mm after treatment. DEX and DO
modified the locomotor facilitation induced by 10 mg/kg PCP in opposite directions.
Data analysis focused on the second half of the test (60-120 min). ANOVA has revealed significant interaction between the dose of sarpogrelate and the dose of dextromethorphan (Figure 11, upper panel; F(9,120)=2.38, P=0.015).
AND ORAL GLUCOSE TOLERANCE: Test substances were administered to male Wistar (Han) rats (180-280 g at the beginning of the experiments; Janvier Labs) housed in groups under free access to food and water. After overnight food deprivation, the tip of the tail was cut, each rat was weighed, housed individually and left without stress in a quiet room.
Approximately 1 hour later, baseline blood glucose was measured from a drop of blood collected from the tail tip, using a commercially available glucose-meter (OneTouch , Lifescan) and then rats received intraperitoneal injection of sarpogrelate and/or dextromethorphan and 30 mm later blood glucose was measured again and rats immediately challenged with glucose at 2 g/kg by oral gavage.
Then, blood glucose was measured at 6 time-points until 180 minutes post-glucose challenge. As shown in Figure 12, there was a main effect of drug treatment (F(4,59=12.0, p<0.0001). Post hoc pairwise group comparisons indicated that, when given alone, dextromethorphan has significantly reduced blood glucose level and this effect of dextromethorphan was reversed when it was administered in combination with sarpogrelate racemate or either of the enantiomers.
RECOVERY TEST USING BEAGLE DOGS (Suzuki et at., Pharmacology & Therapeutics Vol 19 Supplement '91): Compound 50 hydrochloride was given orally to beagle dogs at dose levels of 5, 20, 80 and 320 mg/kg/day for 52 consecutive weeks. No animal died or was sacrificed in extremis regardless of sex. As for general conditions, emesis was noted in males and females receiving 320mg/kg/day and males receiving 80 mg/kg/day and salivation in females receiving 320 mg/kg/day. The body weight gain was inhibited in males and females receiving 320 mg/kg/day.
Food consumption was inhibited in females receiving 80mg/kg/day and over.
Females receiving 320mg/kg/day also showed an inhibition of water consumption. ln the recovery period, the general conditions observed showed no difference between the control and treated groups. There was no treatment related change at electrocardiographic or ophthalmoscopic examination. ln the urinalysis, an increase in protein was revealed in females receiving 320 mg/kg/day, in the hematological examination, an increase in a platelet count in males receiving 320 mg/kg/day, and in the biochemical examination, an increase in potassium in males receiving 80 mg/kg/day and over, and females receiving 320 mg/kg/day. These changes recovered after drug withdrawal. The relative weight of the thyroid and liver was increased in males receiving 80 mg/kg/day and over, but no treatment related change was seen in the histopathological examination.
ln the histopathological examination, fatty degeneration was revealed in the cortico-medullary border zone of the kidney in males receiving 320 mg/kg/day. ln the recovery period however this change was not found. The no effect dose level of compound 50 hydrochloride in a 52-week study was estimated at 20 mg/kg.
All documents referenced above, including, but are not limited to, printed publications, and provisional and regular patent applications, are incorporated herein by reference in their entirety.
NMDA RECEPTOR BLOCKADE IN RATS: To confirm the ability of the present invention (a compound of Formula I) to induce antipsychotic-like effects that are relevant to efficacy against behavioral and psychological symptoms of dementia and that are known for 5-HT2A receptor agonists and inverse agonists, separate groups of rats, housed under standard colony room conditions with free access to food and water, are pretreated with varying doses of deramciclane (up to 30 mg/kg) followed by an NMDA receptor channel blocker or its vehicle and immediately thereafter placed into computer-controlled motor activity recording chambers.
NMDA receptor channel blockers are commonly used in psychopharmacology research on novel therapies including novel antipsychotics. Analysis of variance (ANOVA) is applied to reveal main effects of the deramciclane dose and the interaction between the deramciclane dose and NMDA receptor treatment factors.
OLFACTORY BULBECTOMY IN RATS: In a dedicated set of studies, adult male rats are subjected to bilateral olfactory bulbectomy, a model commonly used to study CNS drugs such as antidepressants. The animals are allowed to recover for at least 14 days following surgery. Sham-operated animals are treated in the same way but the olfactory bulbs are left intact. Prior to each test session, animals are treated with dextromethorphan (up to 60 mg/kg per os) combined with the compound of Formula I (up to 30 mg/kg) and later placed into activitiy monitors for locomotor activity recording. Hyperactivity in rats after olfactory bulbectomy is observed mostly during the early portion of the test sessions. Results are presented as average activity counted over the early portions of test session when activity of the bulbectomized animals is significantly higher than that of the sham controls. ANOVA is applied to reveal significant main effects of both surgery and treatment dose factors. The anti-hyperactivity effects of deramciclane are observed at the doses that do not affect activity of sham-operated rats and therefore do not reflect a generalized non-specific impairment of motor capabilities.
Dextromethorphan 0-demethylase activity is determined in human liver microsomes. The compound of Formula I (concentration: up to 3.0E-5 M) and dextromethorphan are dissolved in acetonitrile and serially diluted with acetonitrile to the required concentrations to give a final organic solvent concentration of about 1.0% in the incubation mixture. The incubation mixtures contain pooled human liver microsomes, dextromethorphan, and a NADPH-generating system.
After incubation and centrifugation, the supernatant is diluted up to 100-fold with acetonitrile and then injected into the LC-MS/MS system. All incubations are performed in triplicate, and mean values are used for analysis. The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) are determined using methods such as non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting. Deramciclane is observed to inhibit CYP2D6-mediated dextromethorphan 0-demethylation.
Sample size is about 80 pl Li-heparin whole blood / time point, i.e. 40 pl Li-heparin plasma / time point. Whole blood samples are stored on ice until centrifugation (10 mm at 3000 g, 4 C). Plasma is prepared within 45 mm after collection, frozen at -20 C and stored at this temperature until processed for LC-MS
analysis. In rats treated with the compound of Formula I, plasma levels of dextromethorphan continue to be high even at the later time points while, in vehicle-treated rats, dextromethorphan levels decline faster.
DISCRIMINATIVE STIMULUS EFFECTS OF DEXTROMETHORPHAN AND
MEMANTINE: Drug discrimination is commonly used to assess interoceptive stimulus control produced by psychoactive drugs (Sukhotina IA et al., Effects of calcium channel blockers on behaviors induced by the N-methyl-D-aspartate receptor antagonist, dizocilpine, in rats. Pharmacol Biochem Behav (1999) 63:569-80). These methods are used to address ability of certain classes of CNS active drugs such as NMDA receptor channel blockers to produce adverse effects (Nicholson KL et al., Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine. Behav Pharmacol (1998) 9:231-43).
receptor channel blockers (Figure 14A) at the dose that had not significantly impair operant performance (Figure 14B). Reduced intensity of discriminative stimulus effects of memantine in the presence of deramciclane (Figure 1, upper panel) indicates that deramciclane can control unwanted effects of NMDA receptor channel blockers such as dextromethorphan (Nicholson KL
et al., Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys.
Psychopharmacology (1999) 146:49-59) not only by inhibiting dextromethorphan' s metabolism (Zawertailo LA et al., Effect of metabolic blockade on the psychoactive effects of dextromethorphan.
Hum Psychopharmacol (2010) 25:71-9) but also by pharmacodynamic mechanisms. Thus, given the 2D6 inhibitory properties of deramciclane, deramciclane most efficiently controls subjective effects of NMDA receptor channel blockers that are metabized via CYP 2D6 such as dextromethorphan.
FORMULA I GIVEN IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL
BLOCKER: Tail suspension is one of the classical tests used to study antidepressant drugs and was also applied to evaluate antidepressant-like effects of NMDA receptor channel blockers (Kos T et al., Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. European Neuropsychopharmacology (2006) 16:297-310). Mice were transferred from the housing room to the testing area in their home cages and allowed to adapt to the new environment for at least 1 h before drug treatment. Immobility was induced by tail suspension whereby mice were attached individually on a paper adhesive tape, 65 cm above the table top. The tape was placed approximately 1 cm from the tip of the tail. Animals were suspended for 6 min and the duration of immobility was recorded. Mice were considered immobile only when they were completely motionless. Prior to the test sessions, there were two injections given; one i.p.
with deramciclane (3 mg/kg) or its vehicle (preinjection time 60 mm) and one with memantine (3 mg/kg), dextromethorphan (10 mg/kg) or saline (preinjection time 30 min).
While given alone none of the treatments at these dose levels had statistically significant effects, combined administration of deramciclane with dextrimethorphan significantly reduced immobility time suggesting antidepressant-like potential of this combination (Figure 15A).
Combination of deramciclane with memantine also reduced immobility time by 57% (P=0.1).
Surprisingly, when a subeffective dose of memantine (3 mg/kg) was given in a combination with another 5-HT2A/2C
receptor antagonist, ritanserin (1 mg/kg), no reduction in immobility time was observed (Figure 15B). Instead, ritanserin was able to reverse antidepressant-like effects of an effective dose of memantine (10 mg/kg). These results suggest that, when given in a combination with NMDA
receptor channel blockers, deramciclane is capable of producing pharmacodynamic effects that distinguish it from at least some of the other representatives of the class of 5-HT2A/2C receptor antagonists and inverse agonists.
I GIVEN IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL BLOCKER:
Conflict tests such as the Geller-Seifter test are commonly used to study anxiolytic effects of drugs and were also applied to evaluate anxiolytic effects of glutamate receptor antagonists (Pietraszek M et al., Anxiolytic-like effects of mGlul and mG1u5 receptor antagonists in rats. Eur J Pharmacol (2005) 514:25-34).
Shock amperage and duration were adjusted for each individual rat. The data were analyzed as response rates (responses per second) during the punished and unpunished components of each session. For analysis purposes, the response rate data obtained during the drug tests were expressed as a response rate change relative to the 5-day baseline. Prior to the test sessions, there were two injections given; one i.p. with deramciclane (1 mg/kg) or its vehicle (preinjection time 60 min) and one with memantine (3 mg/kg) or saline (preinjection time 30 min). Both deramciclane and memantine were given at the dose levels that had on its own any appreciable effects on either punished or unpunished responding (Figures 16A and 16B). However, when subeffective doses of memantine and deramciclane were given in combination, rats were observed to emit significantly more punished responses, indicating synergistic interactions between deramciclane and memantine that result in reduced anxiety.
FORMULA I GIVEN IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL
BLOCKER: Male mice housed in isolation readily develop and demonstrate aggression towards intruders. Such paradigms have been applied to evaluate anti-aggressive of NMDA receptor channel blockers (Belozertseva IV, Bespalov AY, Effects of NMDA receptor channel blockade on aggression in isolated male mice, Aggressive Behavior (1999) 25: 381-396). In these experiments, mice were housed individually and, starting after the first two weeks of isolation, were repeatedly (twice a week) allowed to attack for 4 mm a group-housed stimulus intruder mouse. Only the resident mice that consistently exhibit attack behavior toward intruders were used for the drug tests.
Drug tests began when resident mice demonstrated attacks toward the intruder in at least three consecutive tests and lived in isolation for at least 35 days. Intruder mice were housed in groups of five. Thirty minutes prior to the test, mice were treated with memantine (10 mg/kg) combined with deramciclane (3 mg/kg) or ritanserin (1 mg/kg). When given alone, none of the compounds at the chosen doses exerted any appreciable effects on agonistic behaviors (attacks, bites, threats, tail rattling, upright and sideways posturing, pushing, and retreating).
However, when memantine was combined with deramciclane (but not ritanserin), mice were significantly less likely to attack in the absence of any visible ataxia (Figure 17). Thus, while deramciclane or NMDA receptor antagonists may not be effective when given alone, they can produce robust anti-aggressive properties when given in a combination.
activities? Drug Metab Dispos, 29:1514-1520 ( 2001)) with minor modifications. Recombinant CYP2D6 (0.25 pmol) and HLMs (12.5 ,ug of protein) were used as enzyme sources. An incubation mixture consisted of an enzyme source, dextromethorphan, an NADPH-generating system (500 ,uM NADP, mM glucose 6-phosphate, 10 mM magnesium chloride, and 1 unit/ml glucose 6-phosphate 10 dehydrogenase), and 100 mM potassium phosphate buffer (pH 7.4) in a final volume of 200 pl.
Incubations were performed at 37 C for 10 mM and were terminated by adding 10 p.1 of 70% (w/v) perchloric acid. After removal of protein by centrifugation, 50 pl of the supernatant was subjected to a high-performance liquid chromatography (D7500 integrator, L-7100 pump, L-autosampler, L-7300 column oven, and L-7485 fluorescence detector) equipped with a Mightysil RP-18 GP column (4.6 ,u 250 mm, 5 ,um). The mobile phase was the mixture of acetonitrile/methanol: 10 mM potassium phosphate buffer adjusted to pH 3.5 with phosphoric acid (200:160:630). Elution was performed at a flow rate of 1.0 ml/min. The formation of dextrorphan was monitored at an excitation of 280 nm and an emission of 310 nm.
glucose 6-phosphate, 0.41 mM magnesium chloride, and 1 unit/ml glucose 6-phosphate dehydrogenase), and 100 mM potassium phosphate buffer (pH 7.4) in a final volume of 180 pl. After prewarming at 37 C for 5 mM, reactions were initiated by the addition of the NADPH-generating system. After a 20-mM preincubation, 20 p.1 of AMMC solution was added to the preincubation mixture (final substrate concentration, 0.6 p,M). Incubations were conducted under the same manner as described under Enzyme Assays for AMMC 0-demethylase activity. Prediction of In Vivo Drug Interactions for CYP2D6. An estimate of in vivo inhibition potency was determined by the methods of Obach et al. (2006). The maximal unbound hepatic input concentration, Cmax, u, inlet, was determined using the following equation:
Co.u.skixt1t1 = (Cantx D F klQh) Cmax is defined as the maximal systemic concentration, fu is the fraction unbound in the blood, D
is the oral dose, Fa is the fraction of the oral dose absorbed, ka is the first-order absorption rate constant, and Qh is the hepatic blood flow. In the case of marijuana smoking, absorption from the gastrointestinal tract is not taken into account. Thus, the Cmax, u, inlet for inhaled cannabinoids is equal to fu Cmax. The value of fu for cannabinoids is at most 0.05 because 95 to 99% of plasma THC is bound to plasma proteins, mainly lipoproteins (Grotenhermen, 2003). A
ratio of the area under the curve (AUC) with inhibitor to control AUC could be estimated using the following equation:
AUCh3JAUC = Iffif.xynix/(1 11h. - fra:CYP2130 In the above equation, AUC inhibited is the area under the curve for a given substrate probe in the presence of an inhibitor, and AUCcontroi is the area under the curve for the same probe substrate without inhibitor. The fraction of metabolism of the probe substrate by CYP2D6 and the magnitude of the potency of the inhibitor are represented by fm(CYP2D6) and Ki, respectively.
The value of unity was used for the fm(CYP2D6) of dextromethorphan/dextrorphan urinary ratio (Obach et al., 2006). Thus, a ratio of AUCinhibited to AUCcontrol of dextromethorphan is equal to 1 + III1vivo/Ki.
The AUC values of H-3-labelled compound 829 determined in subacute experiments predominated over C-14; the ratios were 50 to 60 in all brain regions. The enterohepatic cycle, seen after a single dose, also operated after repeated dosage. The time related concentrations of compound 829 in the hypophysis were at least two times higher than that in the plasma and the brain tissues. No significant difference was seen in the concentrations of compound 829 in the symmetrical (left and right) regions of the brain (Magyar et al., Distribution Of Deramciclane In Rat-Brain Regions, European journal of drug metabolism and pharmacokinetics, 23(2), pp. 125-131 (1998), incorporated in entierity).
131-11ketanserin in the absence or presence of the test compound in a buffer containing 50 mM Tris-HC1 (pH 7.4). Nonspecific binding was determined in the presence of 1 pM
ketanserin. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters presoaked with 0.3% PEI and rinsed several times with ice- cold 50 mM Tris-HC1 using a 96-sample cell harvester. The filters were dried then counted for radioactivity in a scintillation counter using a scintillation cocktail (W02005013952A1, EP1500391A 1 [am], incorporated in its enitirety by reference).
After the treatment (15, 30, 45 and 60 mM.) the reaction time was measured again. Animals were regarded as positive if they produced a 2.5-fold reaction time increase at least twice compared to their first control values. Administration of a combination of morphine and compound 129 showed statistically significant analgesic effect over administration of either of the compounds alone (EP1734940 Bl, incorporated in its enitirety by reference).
MEDIATED BY A BIOLOGICALLY ACTIVE METABOLITE: Compound 50 is a peripherally acting 5-HT2A receptor antagonist (Obata H et al., Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral. Eur J
Pharmacol (2000) 404:95-102) and there is a direct evidence generated using 114C1 labeled Compound 50 that sarpogrelate may not be able to cross the blood-brain barrier in the rat (Komatsu T et al., Studies on the Metabolic Fate of (+)-2(Dimethylamino)-1-CCo(m-methoxyphenethyl) phenoxyDmethyllethyl hydrogen siccinate hydrochloride (MCI-9042) (II) :
Absorption, Distribution, Metabolism and Excretion after a Single Administration to Rats).
Claims (15)
receptor inverse agonist, 5-HT2C receptor antagonist, and/or CYP2D6 enzyme inhibitor, the composition comprising:
a) a compound of Formula I:
wherein, R1 and R2 are independently H, substituted or unsubstituted C1-alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C3-10 cycloalkyl-C5-10 aryl, substituted or unsubstituted C4-10 bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-C5-10 aryl, substituted or unsubstituted C4-10 bicycloalkyl-C5-10 heteroaryl, or substituted or unsubstituted C5-10 heteroaryl, or R1 and R2 together with the nitrogen form a saturated or unsaturated heterocycle having one or more hetero atoms selected from N, O, and S; R3 is independently H, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C5-10 heteroaryl, substituted or unsubstituted C3-10 cycloalkyl-C5-10 aryl, substituted or unsubstituted C4-bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-C5-10 aryl, substituted or unsubstituted C4-10 bicycloalkyl-C5-10 heteroaryl or substituted or unsubstituted C5-10 heteroaryl;
n is an integer from 0 to 5; R4 is H, NH-R5, S-R5, -OH, O-R5, ¨CO-R5, ¨O-CO-R5, or ¨CO-O-R5, wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or enantiomers thereof, metabolites thereof, derivatives thereof, prodrugs thereof, acid addition salts thereof, pharmaceutically acceptable salts thereof, or N-oxides thereof; or a combination thereof; and b) a compound of Formula II, wherein, R6, R7, and R8 are independently H, D, C1-10-alkyl, halo C1-10-alkyl wherein halogen is F, Cl, or Br; R9 and R10 are independently H; C1-10-alkyl; halo C1-10-alkyl wherein halogen is F, Cl, or Br; OH; or R9 and R10 together form a five-membered heterocycle wherein the hetero atom is O, S, or N; enantiomers, metabolites, derivatives, prodrugs, salts, diastereomers, pharmaceutically acceptable salts, or N-oxides thereof, or a combination thereof; or enantiomers thereof, metabolites thereof, derivatives thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or acid addition salts, or a combination thereof.
magnesium; (2S,4R)-4-(phosphonomethyl)piperidine-2-carboxylic acid; (E)-1-(3-ethylphenyl)-1-methyl-2-(naphthalen-1-yl)guanidine; 2-phenylpropane-1,3-diyl dicarbamate: 1-(1-phenylcyclohexyl)piperidine; 1-aminoadamantine; 3,5 dimethylaminoadamantone;
4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid; (R)-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid; (R)-2-amino-5- phosphonopentanoate; (S) and (R) 6-(1HTetrazol-5-ylmethyl)decahydroisoquinoline-3-carboxylic acid; (S)-a-amino-5-(phosphonomethyl)[1,19-biphenyl]-3-propanoic acid; (S)-(6)-cis-4-(4-phenylbenzoyl) piperazine-2,3-dicarboxylic acid; (R)- (6)-cis-4-(4-phenylbenzoyl) piperazine-2,3-dicarboxylic acid; cis-4-phosphonomethyl-2-piperidine carboxylic acid; 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid); or cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid; or enantiomers thereof, metabolites thereof, derivatives thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or acid addition salts; or a combination thereof.
4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-3,3-difluoro-4-oxobutanoic acid;
(S)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-3,3-difluoro-4-oxobutanoic acid;
(R)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-3,3-difluoro-4-oxobutanoic acid;
4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-4-oxobutanoic acid;
(S)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-4-oxobutanoic acid;
(R)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-4-oxobutanoic acid;
4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid;
(S)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid;
(R)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid;
4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3,3-trifluoro-4-oxobutanoic acid;
(S)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3,3-trifluoro-4-oxobutanoic acid;
(R)-4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3,3-trifluoro-4-oxobutanoic acid;
2-phenyl-2-(2-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-phenyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(p-methoxy-phenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzyl-2-(3'-dimethylamino-21-methylpropoxy)-1,7,7-trimethyl-bicyclo[2,2,1]
heptane;
2-benzyl-2-(2-diisopropylaminoethoxy)-1,7,7-trimethyl-bicyclo[2,2,1]heptane;
2-benzyl-2-1'-(4'-benzylpiperazinyl)-propoxyl,7,7-trimethylbicyclo[2,2,1]
heptane;
2-benzyl-2-(3'-diisopropylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2,2,1]heptane;
2-benzyl-2-(2'-diethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-(4'-methoxyphenyl)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(p-chloro-benzyl)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,1]
heptane;
2-(p-chloro-benzyl)-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylamino-2'-methyl)-propoxy-2-(p-chloro-phenyl)-1,7,7-trimethylbicyclo[2,2,1]
heptane;
2-(3'-dimethylaminopropoxy)-2-phenyl-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(2'-dimethylaminoethoxy)-2-phenyl-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(3-diethylaminopropoxy)-2-phenyl-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(2'-diethylaminoethoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(3'-diethylaminopropoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzyl-2-3'-(N-cyclohexyl-N-methyl)aminopropoxy]-1,7,7-trimethylbicyclo[2,2,1] heptane;
2-(p-methoxyphenyl)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,1]
heptane;
(1R,2S,4R)-(-)-2-[(2'- N,N-dimethylamino 1 -ethoxy)] -2- [phenyl] - 1,7,7-trimethylbicyclo [2,2,1]
heptane;
(1R,2S,4R)-(-)-2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1] heptane;
(1R,2S,4R)-(-)-2-benzyl-2-(2'-methyl-3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo [2,2,1]
heptane;
(1RS,2RS,4RS)-2-phenyl-2-(2'-dimethylaminoethoxy)-1,7,7 trimethylbicyclo[2,2,1] heptane;
(1S,2R,4S)-(+)-2-phenyl-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]
ethanamine.; ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl isopropyl (S)-phosphorofluoridate;
(((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy) methyl isopropyl (S)-phosphorofluoridate;
(((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl isopropyl (S)-phosphorofluoridate;
((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl (3,3-dimethylbutan-2-yl) (R)-phosphorofluoridate;
sec-butyl ((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
sec-butyl ((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl O-(4-nitrophenyl) phosphorothioate;
Compound 908 O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl O-(4-nitrophenyl) phosphorothioate;
O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl O-(4-nitrophenyl) phosphorothioate;
O-((( 1 -(dimethyl amino)- 3 -(2-(3 -methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) S -(( 1 ,3-dioxoisoindolin-2-yl)methyl) (dimethyl-13-oxidaneyl)phosphonodithioate;
O-((((S)- 1 -(dimethylamino)-3 -(2-(3 -methoxyphenethyl )phenoxy)propan-2-yl)oxy)methyl) S -(( 1 ,3 -dioxoisoindolin-2-yl)methyl) (dimethyl-13 -oxidaneyl)phosphonodithioate;
O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) S-(( 1 ,3 -dioxoisoindolin-2-yl)methyl) (dimethyl-13 -oxidaneyl)phosphonodithioate;
(E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl ((( 1 -(dimethylamino) -3 -(2-(3 -methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) methyl phosphate;
(E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl ((((S)- 1 -(dimethylamino)-3 -(2- (3 -methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) methyl phosphate;
(E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl ((((R)- 1 -(dimethylamino)-3 -(2- (3 -methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) methyl phosphate O-((( 1 -(dimethyl amino)- 3 -(2-(3 -methoxyphenethyl) phenoxy)propan-2-yl)oxy) methyl) S -(2-(ethylsulfinyl)ethyl) O-methyl phosphorothioate;
O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-(2-(ethylsulfinyl)ethyl) O-methyl phosphorothioate;
O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-(2-(ethylsulfinyl)ethyl) O-methyl phosphorothioate;
O-(((1-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl) O-ethyl S-((ethyl thio)methyl) phosphorodithioate;
O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) O-ethyl S-((ethylthio)methyl) phosphorodithioate;
O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) O-ethyl S-((ethylthio)methyl) phosphorodithioate;
S-((6-chloro-2-oxobenzo [d]oxazol-3 (2H)- yl)methyl) O-( (( 1 - (dimethylamino) -3 -(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
S-((6-chloro-2-oxobenzo [d]oxazol-3 (2H)- yl)methyl) O-((((S)- 1 -(dimethylamino) -3 - (2-(3 -methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
S-((6-chloro-2-oxobenzo [d] oxazol-3 (2H)- yl)methyl) O-((((R)- 1 -(dimethyl lamino) -3 -(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
S-((tert-butylthio)methyl) O-(((1-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
S-((tert-butyl thio) methyl) O-((((S)-1- (dimethyl amino) -3-(2- (3-methoxy phen ethyl) phenoxy) propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
S-((tert-butylthio) methyl) O-((((R)-1- (dimethyl amino)- 3-(2-(3-methoxy phen ethyl) phenoxy) propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
O-(4-((4-(((((1-(dimethyl amino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) phosphorothioyl) oxy) phenyl) thio) phenyl) O,O-dimethyl phosphorothioate;
O-(4-((4-((((((S)-1- (dimethylamino) -3-(2-(3-methoxy phenethyl) phenoxy) propan- 2-yl) oxy) methoxy) (methoxy) phosphorothioyl) oxy) phenyl) thio) phenyl) O,O-dimethyl phosphorothioate;
O-(4-((4-((((((R)- 1 - (dimethyl amino)-3 -(2-(3 -methoxyphenethyl) phenoxy)propan-2-yl)oxy) methoxy) (methoxy) phosphorothioyl) oxy) phenyl) thio) phenyl) O,O-dimethyl phosphorothioate;
((1-(dimethylamino) -3-(2- (3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl triethyl diphosphate;
(((S)-1- (dimethylamino) -3-(2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl triethyl diphosphate;
(((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl triethyl diphosphate;
((1-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate;
(((S)-1-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate;
(((R)-1-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate;
2-chloro-1- (2,4,5-trichlorophenyl) vinyl (((1-(dimethylamino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl)oxy) methyl) hydrogen phosphate;
2-chloro-1-(2,4,5-trichlorophenyl) vinyl ((((S)-1-(dimethyl amino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
2-chloro-1-(2,4,5-trichlorophenyl) vinyl ((((R)-1-(dimethyl amino)-3-(2-(3-methoxy phene thyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
O-(((1-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl) S-methyl acetylphosphoramidothioate;
O-((((S)-1-(dimethylamino) -3-(2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methyl acetyl phosphoramidothioate;
O-((((R)-1- (dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl) S-methyl acetylphosphoramidothioate;
(O-((( 1 -(dimethylamino)-3 -(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-propyl phosphorothioic) (O,O-dipropyl phosphorothioic) anhydride;
(O-((((S)-1-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) O-propyl phosphorothioic) (O,O-dipropyl phosphorothioic) anhydride;
(O-((((R)-1-(dimethyl amino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propyl phosphorothioic) (O,O-dipropyl phosphorothioic) anhydride;
O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-methyl acetylphosphoramidothioate;
O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-methyl acetylphosphoramidothioate;
O-((((R)-1-(dimethylamino)-3-(2-(3-methoxy phenethyl)phenoxy)propan-2-yl) oxy) methyl) S-methyl acetylphosphoramidothioate;
O-((( 1 -(dimethylamino)-3-(2-(3 -methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-methyl S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl) phosphorodithioate compound with methane (1:1);
O-((((S)- 1 -(dimethylamino)-3 -(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-methyl S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl) phosphorodithioate compound with methane (1:1);
O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-methyl S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl) phosphorodithioate compound with methane (1:1);
2-chloroethyl ((( 1 -(dimethylamino)-3-(2-(3 -methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
2-chloroethyl ((((S)- 1 -(dimethyl amino)-3 -(2-( 3 -methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
2-chloroethyl ((((R)- 1 -(dimethylamino)-3-(2-(3 -methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
3 -chlorobutan-2- yl ((( 1 -(dimethylamino)-3-(2-(3 -methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
3-chlorobutan-2-yl ((((S)-1-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
3-chlorobutan-2-yl ((((R)-1-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
((1 -(dimethylamino)-3 -(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl (S)-((((E)-chlorofluoromethylene)amino)oxy)phosphonofluoridate;
((((S)- 1 -(dimethylamino)- 3 -(2-(3 -methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl (S)-((((E)-chlorofluoromethylene)amino)oxy)phosphonofluoridate;
((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl (S)-((((E)-chlorofluoromethylene)amino)oxy)phosphonofluoridate;
2-chloroethyl ((( 1 -(dimethylamino)-3-(2-(3 -methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene) amino)oxy)phosphorofluoridate;
2-chloroethyl ((((S)- 1 - (dimethyl amino)-3 -(2- (3 -methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphorofluoridate;
2-chloroethyl ((((R)- 1 -(dimethyl amino) -3 -(2- (3 -methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphorofluoridate;
1 -chloropropan-2- yl ((( 1 -(dimethylamino)-3-(2-(3 -methoxyphenethyl) phenoxy) propan-2- yl) oxy)methyl) (E)-(((chlorofluoromethylene)amino)oxy) phosphorofluoridate;
1 -chloropropan-2- yl ((((S)- 1 -(dimethylamino)-3 -(2- (3 -methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene) amino)oxy) phosphoro fluoridate;
1-chloropropan-2-yl ((((R)-1-(dimethylamino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl) oxy)methyl) (E)-(((chlorofluoro methylene) amino) oxy) phosphoro fluoridate;
3 -chlorobutan-2- yl ((( 1 -(dimethylamino)-3 -(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphorofluoridate;
3-chlorobutan-2-yl ((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphoro fluoridate;
3-chlorobutan-2-yl ((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene) amino)oxy) phosphoro fluoridate.
((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate.
((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate;
((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate.
4-(tert-butyl)-2-chlorophenyl ((( 1 -(dimethylamino)-3 -(2-(3 -methoxyphenethyl) phenoxy)propan-2- yl)oxy)methyl) methylphosphoramidate compound with methane (1:1);
4-(tert-butyl)-2-chlorophenyl ((((S)- 1 -(dimethylamino)-3-(2-(3 -methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) methylphosphoramidate compound with methane (1:1).
4-(tert-butyl)-2-chlorophenyl ((((R)- 1 - (dimethylamino)-3 -(2- (3 -methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) methylphosphoramidate compound with methane (1:1).
((1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4-(methylthio) phenyl) isopropylphosphoramidate;
((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy) methyl (3-methyl-4-(methylthio)phenyl) isopropylphosphoramidate.
((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-yl)oxy) methyl (3-methyl-4-(methylthio)phenyl) isopropylphosphoramidate;
((2( )-[1R,2S,4R] -2- (2-dimethyl amino ethoxy) -2- phenyl -1,7,7- trimethyl bicyclo [2.2.1]
heptane) fumarate;
and wherein the compound of Formula II is an NMDA Receptor Antagonist selected from the group consisting of: ketamine; methadone; memantine; amantadine;
dextropropoxyphene;
ketobemidone; dextromethorphan; (4bS,8aS,9S)-11-methyl-3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene;
(4bS,8aS,9S)-3-(trifluoromethoxy)-11-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene; or (4bS,8aS,9S)-3-methoxy-11-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano) phenanthrene; or an acid addition salt selected from acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate glutarate, hydrobromide, hydrochloride, isophthallate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthallate, salicylate, sebacate, succinate, terephthallate, tyrosinate, tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-tyrosinate, N-acyl-tryptophanate, N-acyl-methionate, citrate, galactonate, glucaric acid (saccharic acid), mannonate, mucate, rhamnonate, and tartrate; or a combination thereof.
polymer, b. emulsifier, c. binder, d. a disintegrating agent, and/or e. a lubricant.
or an acid addition salt thereof, selected from acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate glutarate, hydrobromide, hydrochloride, isophthallate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthallate, salicylate, sebacate, succinate, terephthallate, tyrosinate, tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-tyrosinate, N-acyl-tryptophanate, N-acyl-methionate, citrate, galactonate, glucaric acid (saccharic acid), mannonate, mucate, rhamnonate, and tartrate; or a combination thereof.
polymer, b. emulsifier, c. binder, d. a disintegrating agent, and/or e. a lubricant.
(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-((3,5-dimethyl adamantan-1-yl) amino) -4- oxobutanoate; (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2- yl 4-((3,5-dimethyl adamantan-1-yl) amino) -4- oxobutanoate; 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl (2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl) succinate; (S)-1- (dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl (2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl) succinate; (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl (2,2,2-trichloro-1-(dimethoxyphosphoryl) ethyl) succinate; 3 ,5-dimethyladamantan-1- amine; or dimethyl (2 ,2,2-trichloro-1-hydroxyethyl)phosphonate.
plasma levels in a subject in need thereof of, wherein the subject is an extensive metabolizer of DEX, the method comprising administering the composition.
a) administering a therapeutically effective amount of the composition of claim 7;
b) targeting CYP2D6 enzyme and NMDA, 5-HT2A, and 5HT2C receptors;
c) treating a neuropsychiatric or neurodegenerative disease or disorder, or brain injury, comprising behavioral and psychological symptoms of dementia (BPSD), in a patient in need thereof; and d) producing a symptomatic relief and/or disease modification.
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WO2020246143A1 (en) * | 2019-06-06 | 2020-12-10 | Jsr株式会社 | Radiation-sensitive resin composition, resist pattern formation method, and compound |
CN115667217A (en) | 2020-05-19 | 2023-01-31 | 赛本爱尔兰有限公司 | Deuterated tryptamine derivatives and methods of use |
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US4241065A (en) * | 1979-07-02 | 1980-12-23 | E. I. Du Pont De Nemours And Company | Fluoro analogs of hydrocodone and oxycodone useful as analgesics, narcotic antagonists or both |
US4950658A (en) * | 1988-12-06 | 1990-08-21 | Board Of Trustees Of Southern Illinois Univ. | Method of medical treatment of Alzheimer's disease |
US5891885A (en) | 1996-10-09 | 1999-04-06 | Algos Pharmaceutical Corporation | Method for treating migraine |
US6207674B1 (en) | 1999-12-22 | 2001-03-27 | Richard A. Smith | Dextromethorphan and oxidase inhibitor for weaning patients from narcotics and anti-depressants |
US6335371B1 (en) * | 2000-11-28 | 2002-01-01 | Orion Corporation | Method for inducing cognition enhancement |
TWI326214B (en) | 2002-07-17 | 2010-06-21 | Avanir Pharmaceuticals Inc | Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders |
US20070099947A1 (en) * | 2005-11-03 | 2007-05-03 | Alkermes, Inc. | Methods and compositions for the treatment of brain reward system disorders by combination therapy |
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US8017623B2 (en) * | 2008-07-03 | 2011-09-13 | Trinity Laboratories, Inc. | Dextromethorphan hydrochloride |
US9737531B2 (en) * | 2012-07-12 | 2017-08-22 | Glytech, Llc | Composition and method for treatment of depression and psychosis in humans |
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BR112019022902A2 (en) | 2020-05-19 |
CN110831584B (en) | 2023-03-10 |
JP2023143940A (en) | 2023-10-06 |
TWI787260B (en) | 2022-12-21 |
RU2019137004A (en) | 2021-06-04 |
KR102444803B1 (en) | 2022-09-19 |
EP3618819A4 (en) | 2021-01-20 |
CA3138116A1 (en) | 2018-11-08 |
AU2018261654A1 (en) | 2019-11-14 |
KR20200062078A (en) | 2020-06-03 |
RU2760558C2 (en) | 2021-11-29 |
JP2020518617A (en) | 2020-06-25 |
JP7514078B2 (en) | 2024-07-10 |
IL270326B (en) | 2022-10-01 |
AU2021215274A1 (en) | 2021-09-02 |
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RU2019137004A3 (en) | 2021-06-04 |
TW201842902A (en) | 2018-12-16 |
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