AU2008201372A1 - Ph-Dependent NMDA receptor antagonists - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A DIVISIONAL PATENT

ORIGINAL

Name of Applicant: EMORY UNIVERSITY Actual Inventor(s): Raymond J. DINGLEDINE, Dennis C. LIOTTA, Stephen F.

TRAYNELIS and James P. SNYDER Address for Service: Houlihan 2 Level 1, 70 Doncaster Road, Balwyn North, Victoria 3104, Australia Invention Title: PH-DEPENDENT NMDA RECEPTOR ANTAGONISTS The following statement is a full description of this invention, including the best method of performing it known to

IA

PH-DEPENDENT NMDA RECEPTOR ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. patent application no. 60/274,205, filed March I 8, 2001, which is incorporated herein by reference to the extent not inconsistent herewith.

SBACKGROUND

0 NMDA receptors are a subtype of glutamate-gated ion channels that mediate excitatory synaptic transmission between neurons in the central nervous system (Dingledine, R. et al., [1999], "The glutamate receptor ion channels," Pharmacological Reviews 51:7-61).

NMDA receptors are a subtype of the most widespread excitatory neurotransmitter receptor in the brain. Excessive activation of NMDA receptors kills neurons, and current evidence implicates NMDA receptor activation in a variety of neurologic disorders that include epilepsy, ischemic brain damage, traumatic brain/spinal cord injury, and Alzheimer's Diseases, Huntington's chorea and Amyotrophic Lateral Sclerosis (ALS).

In animal models of stroke and brain trauma, glutamate released from affected neurons can overstimulate NMDA receptors, which in turn causes neuronal death. Because overactivation of NMDA receptors is neurotoxic, compounds that block NMDA receptors have been considered candidates for treatment of stroke or head injuries. Numerous animal studies have validated NMDA receptors as targets for neuroprotection in stroke, brain and spinal cord trauma, and related settings that involve brain ischemia. NMDA receptor blockers are effective in limiting the volume of damaged brain tissue in experimental models of stroke and traumatic brain injury. (Choi, D. (1998), "Antagonizing excitotoxicity:

A

therapeutic strategy for stroke," Mount Sinai J. Med. 65:133-138; Dirnagle, U. et al. (1999) "Pathobiology of ischaemic stroke: an integrated view," Tr. Neurosci. 22:391-397; Obrenovitch, T.P. and Urenjak, J. (1997) "Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury," J. Neurotrauma 14:677-698.) In addition, NMDA receptor antagonists are known to be anti-convulsant in many experimental models of epilepsy (Bradford, H.R. [1995] "Glutamate, GABA, and Epilepsy," Progress in Neurobiology 47:477-511; McNamara, J.O. [2001] Drugs effective in the therapy of the WO 02/072542 PCT/US02/07033 0 2 S epilepsies. In Goodman Gliman's: The pharmacological basis of therapeutics [Eds. J.G.

t Hardman and L.E. Limbird] McGraw Hill, New York). However, dose-limiting side effects have thus far prevented clinical use of NMDA receptor antagonists for these neurologic S conditions (Muir, K.W. and Lees, K.R. [1995] "Clinical experience with excitatory amino acid antagonist drugs," Stroke 26:503-513; Herrling, ed. [1997] "Excitatory amino acid clinical results with antagonists" Academic Press; Parsons, C.G. et al. [1998] "Glutamate in CNS disorders as a target for drug development: an update," Drug News Perspective 11:523- 569), and consequently enthusiasm for this receptor protein as a drug target has diminished within the pharmaceutical industry. NMDA receptor blockers also act synergistically with L- DOPA to relieve symptoms of Parkinsonism. In addition, such compounds are useful for treating chronic neuropathic pain and bipolar disorder. However, the first three generations of NMDA receptor antagonists (channel blockers, competitive blockers of the glutamate or glycine agonist sites, and noncompetitive allosteric antagonists) have not proved useful clinically.

Several recent papers have suggested that rapidly-growing brain gliomas can kill adjacent neurons by secreting glutamate and overactivating NMDA receptors The dying neurons make room for the growing tumor, and may release cellular components that stimulate tumor growth. These studies shown NMDA receptor antagonists can reduce the rate of tumor growth in vivo as well as in some in vitro models. (Takano, et al. (2001), "Glutamate release promotes growth of malignant glioma," Nature Medicine 7:1010-1015; Rothstein, J.D. and Bren, H. (2001), "Excitotoxic destruction facilitates brain tumor growth," Nature Medicine 7:994-995; Rzeski, et al. (2001), "Glutamate antagonists limit tumor growth," Proc. Nat'l Acad. Sci 98:6372-6377.) In the late 1980's a new class of NMDA receptor antagonists (phenylethanolamines) was discovered which did not bind at the agonist binding sites. This class, exemplified by the compound ifenprodil, selectively interacts with NMDA receptors containing the NR2B subunit. These compounds have exhibited neuroprotective properties in preclinical models.

This class of antagonist lacks the severe side-effect liability of other types of NMDA antagonists PCP-like psychotic symptoms and cardiovascular effects).

WO 02/072542 PCT/US02/07033 3 C One of the most prevalent subtypes of NMDA receptor which contains the NR2B S subunit has the unusual property of being normally inhibited by protons by about 50% at Sphysiological pH (Traynelis, S.F. and Cull-Candy, S.G. [1990] "Proton inhibition of Nmethyl-D-aspartate receptors in cerebellar neurons," Nature 345:347-350. We have found that phenylethanolamines, typified by ifenprodil and CP 101,606 inhibit activation of NMDA receptors by potentiating allosteric inhibition mediated by protons. In turn, small reduction of pH in the physiological range increases the potency of some phenylethanol-amines as NMDA 00 receptor antagonists. The potency of ifenprodil for inhibition of NR2B subunit-containing recombinant NMDA receptors is enhanced at pH 6.8 compared to pH 7.5. (Mott et al.

[1998], "Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition," Nature Neuroscience 1(8):659-667.) Ischemic brain tissue, as well as the site of seizure generation in epilepsy, is characterized by a lower pH than is found in brain tissue.

Therapeutic compounds for the foregoing pathologies may have toxic side effects. It is thus an object of this invention to provide compounds which have enhanced activity under the lower pH conditions characteristic of such pathologies, and which are less active under the normal pH conditions of healthy brain tissue.

A number of patents discuss NMDA receptor antagonists, including U.S. Patents 6,080,743 to Acklin et al.; 4,924,008 and 4,957,909 to Abou-Gharbia et al.; 5,889,026, 5,952,344, 6,071,929, 6,265,426, and 6,339,093 to Alanine et al.; 5,633,379 to Allgeier; 5,922,716, 5,753,657 and 5,777,114 to Aloup et al.; 5,124,319 to Baudy et al.; 5,179,085 to Bigge et al.; 5,962,472 to Bourson et al.; 5,919,826,6,007,841, 6,054,451, and 6,187,338 to Caruso et al.; 5,498,610, 5,594,007, 5,710,168, and 6,258,827 to Chenard et al.; 5,888,996 and 6,083,941 to Farb; 5,981,553 to Farr et al.; 5,866,585, 6,057,373, and 6,294,583 to Fogel; 6,274,633 to Franks et al.; 5,385,947 to Godel et al.; 6,034,134 and 6,071,966 to Gold et al.; 5,714,500 to Griffith et al.; 5,563,157 and 5,606,063 to Harrison et al.; 5,395,822 to Izumi et al.; 5,118,675 to Jirkovsky et al.; 6,177,434 to Kopke et al.; 5,132,313 to Kozikowski et al.; 5,321,012, 5,502,058, 5,556,838, 5,654,281, 5,834,479, 5,840,731, 5,863,922, and 5,869,498 to Mayer et al.; 5,318,985, 5,441,963 and 5,489,579 to McDonald et al.; 6,284,776 to Meltzer; 6,180,786 to Metz, Jr.; 5,783,572 to Mowbray et al.; 6,200,990 to Namil et WO 02/072542 PCT/US02/07033 00 4 c al.;5,783,700 to Nichols et al.; 5,034,400, 5,039,528, 5,474,990, 5,605,911, 5,616,580, 5,629,307, 5,767,130, 5,834,465, 5,902,815, 5,925,634, and 5,958,919 to Olney et al.; IN 5,990,126 to Park et al.; 5,013,540 to Redburn; 6,025,369 to Rosenquist et al.;5,106,847, 5,189,0545,491,153, 5,519,0485,675,018, and 5,703,107 to Salituro et al.;6,096,743 to Shishikura et al.; 6,242,456 to Shuster et al.; 6,194,00 to Smith et al.; 6,197,820 to Sontheimer et al.; 5,385,903 to Steppuhn et al.; 5,710,139 to Swahn; 5,192,751 to Thor; 5,614,509 to Turski et al.; 4,906,779, 5,093,525, 5,190,976, 5,262,568, 5,336,689, 5,559,154, 0O 5,637,622, 5,767,162, 5,798,390, and 6,251,948 to Weber et al.; 5,095,0095,194,430, S5,326,756, 5,470,844, and 5,538,958 to Whitten; 6,284,774 to Wright et al.;5,587,384 and Re 36,397 to Zhang et al.; and 4,994,467 to Zimmerman. However, NMDA receptor blockers are needed which are enhanced at low pHs characteristic of certain pathological conditions for treatment of such pathological conditions.

All publications referred to herein are incorporated by reference to the extent not inconsistent herewith.

SUMMARY

This invention provides NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, as neuroprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue.

Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower-than-normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia that may occur during cardiac surgery, hypoxia that may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, status epilepticus, neuropathic or inflammatory pain, chronic pain, vascular dementia and glioma tumors. Because tumors produce an acidic environment, drugs activated by low pH are useful in slowing tumor growth because they have enhanced activity only at the site of the tumor. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson's Alzheimer's, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using WO 02/072542 PCT/US02/07033 00 O

O

C NMDA receptor blockers. Preferably the compounds provided herein are allosteric NMDA t inhibitors.

Also preferably, the compounds provided herein are selective NMDA receptor blockers, that is, they do not interact with other receptors or ion channels at therapeutic concentrations. General blocking of NMDA receptors throughout the brain causes adverse effects such as ataxia, memory deficits, hallucinations and other neurological problems.

00 o 0 The compounds provided herein block the NR2B-containing NMDA receptors, have varying activity against receptors containing NR2A or NR2D, and may be selective for other members of the NMDA receptor family (NR2C, NR3A and NR3B).

The novel small molecule NMDA receptor antagonists of this invention are useful both in the treatment of stroke and head trauma in the emergency room setting, and for use as prophylactic agents for at risk patients. The acid generated by ischemic tissue during stroke is harnessed as a switch to activate the neuroprotective agents described herein. In this way side effects are minimized in unaffected tissue since drug at these sites are less active. These compounds reduce the amount of neuronal death associated with stroke and head trauma.

These compounds also have military uses as a neuroprotective for battlefield head trauma.

They may be given chronically to individuals with epilepsy or who are at risk for stroke or head trauma, preoperatively in high risk heart/brain surgery, etc., in order to lengthen the window of opportunity for subsequent therapy.

This invention provides the following useful for treating conditions characterized by lowered brain-tissue pH, selected from the group consisting of and (S)-enantiomers and mixtures thereof of compounds of the formula:

A-B-

WO 02/072542 PCT/US02/07033 6 wherein one of IR, Ro,, RI, R, and Ris is 0 R13 R17 where is alkyl, aralkyl or aryl; where R 1 7 is H or lower alkyl; and the others of R 9 Ro, R, 2 and are H, F, Cl, I or R wherein R is lower alkyl; or: Pe 0 R1 3 A-B-

\\O

12 R11 wherein R 9

R,

0 and Ri 2 are independently selected from the group consisting of H, F, Cl, Br, I, and R wherein R is lower alkyl, and R, 3 is alkyl aralkyl or aryl; wherein A is selected from the group consisting of: wherein R, and R, are independently H or F; R 2

R

3 and R 4 are independently selected from the group consisting of H, F, CI, Br, I and OR where R is lower alkyl, or R, and

R

3 taken together are O-CH 2

-O;

WO 02/072542 PCT/US02/07033 wherein R 4 and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, R 3 is independently O, S, NH or NR, R, is N, and R, 6 is C-alkyl, C-aralkyl or C-aryl; wherein R 4 and R, are independently selected from the group consisting of H, F, CI, Br, I and OR where R is lower alkyl, R 2 is independently O, S, NH or NR, R 3 is N; and R, 6 is C-alkyl, C-aralkyl or C-aryl; wherein R, through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, or R 2 and R 3 taken together are O-CH,-O; WO 02/072542 PCT/US02/07033 8 O R3 Io R R4

R,

CM wherein R 2 and R 3 are independently selected from the group consisting of O, S, 00 NH or NR where R is lower alkyl, or R 2 and R 3 taken together are O-CH 2 and R 4 is

N;

RR\

R R4 wherein R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; and R 4 is N;

R

3 R4 R2 R1 wherein R, is selected from the group consisting of O, S, NH and NR where R is lower alkyl; R 2 is N, and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R3 "64 R2\ WO 02/072542 PCT/US02/07033 00 O 9 s wherein R, is selected from the group consisting of O, S, NH and NR where R is lower alkyl; R 2 and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R3, 00 wherein R, is selected from the group consisting of O, S, NH and NR where R is lower alkyl; R 2 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; and R 3 and R 4 are N; R3

R

wherein R, is selected from the group consisting of O, S, NH and NR where R is lower alkyl; and R 2

R

3 and R 4 are N; R2' R3 I R4

R

wherein R, and R 3 are independently selected from the group consisting of O, S, NH and NR where R is lower alkyl; and R 2

R

2 and R 4 are independently selected from the group consisting of H, F, CI, Br, I and OR where R is lower alkyl; WO 02/072542 PCT/US02/07033 wherein R, and R2 are independently selected from the group consisting of O, S, NH and NR where R is lower alkyl; and R2', and R 3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl;

RI

wherein X, is C-R 3 or N, X 2 is C-R 4 or N, X 3 is C-R 4 or N where R,-R 4 are independently selected from the group consisting of O, S, NH and NR where R is lower alkyl, or where R, and R 2 taken together are O-CH 2

-O;

and wherein B is selected from the group consisting of: H H R6 R7 R8 wherein R 6 and R6' are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar,

CH

2

CH

2 Ar, CH 2 CHFAr, or CH 2

CHF

2 Ar; and R, is OH, OR, where R is lower alkyl, or F; WO 02/072542 PCT/US02/07033 11 0 SH

H

R6' R

R

wherein R and R 6 are independently H or F; R 7 is CH, and R 8 is O; C-i R.6 co- 00 R8 wherein R. and R 7 are independently CH 2 CHR or CR, where R is lower alkyl; and R, is OH, OR, where R is lower alkyl, or F; H H R R7 R8

(CH

wherein R. and R, are independently CH 2 CHR or CR 2 where R is lower alkyl; and R, is OH, OR, where R is lower alkyl, or F; (CH2)n H H Re R7 R8 wherein RP and R 7 are independently CH 2 CHR or CR2 where R is lower alkyl; R, is OH or F; and n=1-3; and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.

WO 02/072542 PCT/US02/07033 00 O 12

O

These compounds are preferably provided in combination with a suitable pharmaceutical carrier.

IND

Preferred compounds of this invention include and enantiomers and mixtures thereof of compounds selected from the group consisting of:

C"

0 R4 0 0 R O R

R

9 10 Q

R

1 Re R 6 R7 R 8 R12 R11 wherein R, and R, are independently H or F; and when R, and R, are H, R 2

R

3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and R 2 and R 3 taken together are O-CH 2 R, and are independently H or F; R 7 is selected from the group consisting of lower n-alkyl, CH 2 Ar, CH 2

CH

2 Ar, CH 2 CHFAr and CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 RI, and R, 2 are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; and R,3 is alkyl, aralkyl or aryl; and when one of R, or R, is F and the other is H or F, R 2

R

3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl and R 2 and R 3 taken together are O-CH 2 R, and are independently H or F; R 7 is selected from the group consisting of H, lower n-alkyl,CH 2 Ar, CH 2

CH

2 Ar,

CH

2 CHFAr and CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- WO 02/072542 PCT/US02/07033 13 pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; RI,, R, and R,, are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; and R,3 is alkyl, aralkyl or aryl;

R

6 Re6 wherein R, and R, are independently H or F; R, is N; R 3 is O, S, NH or NR where R is lower alkyl; R 4 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, R. and R' are independently H or F; R 7 is selected from the group consisting of H, lower n-alkyl, CH 2 Ar, CH 2

CH

2 Ar, CH 2 CHFAr and CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4trifluorophenyl, or 2 3 4 ,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; Ro, and R 2 are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; is alkyl, aralkyl or aryl; and R, 6 is C-alkyl, C-aralkyl or C-aryl; wherein R, and R, are independently H or F; R, is independently O, S, NH or NR where R is lower alkyl; R 3 is N; R 4 is selected from the group consisting of H, F, Cl, Br, I and OR wherein R is lower alkyl, RP and R6' are independently H or F; R 7 is selected from the group WO 02/072542 WO 02172542PCT/US02/07033 14 consisting of H, lower n-alkyl,CH 2 Ar, CH 2

CH

2 Ar, CH 2 CHFAr and CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, wvhere R. is lower alkyl, or F;

R

9 1 Rj 0

R

11 and R 1 2 are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and R, 6 is C-alkyl, C-aralkyl, or C-aryl; wherein R, through R, are independently selected from the group consisting of H, F, Cl, Br, I and and R 2 and R 3 taken together are O-CH 2 P. and R.'are independently H or F; R 7 is CH 2 R, is 0; R 9 RIO, R I, and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; R 14 is C-alkyl, C-aralkyl or C-aryl; and R, 5 is lower alkyl; wherein R 4 and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 2 is 0, S, NH or R 3 is N; R. and R,' are independently H or F; R 7 is CH 2 R, isO0; R(9, Rio, RI and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, WO 02/072542 PCT/USO2/07033 aralkyl or aryl; is lower alkyl; and R, 6 is C-alkyl, C-aralkyl or C-aryl;

R

1

R

6

R

6 7 wherein R 4 and R, are independently selected from the group consisting of H, F, CI, Br, I and OR where R is lower alkyl; R 2 is N; R 3 is O, S, NH or NR,s; R 6 and R.' are independently H or F; R 7 is CH 2 R, is O, R 9 Ro, and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R,, 3 is alkyl, aralkyl or aryl; is lower alkyl; and R, 6 is C-alkyl, C-aralkyl or C-aryl; wherein R, and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR 14

R

2 and R 3 are independently selected from the group consisting of F, Cl, Br, I, and OR,4, and R 2 and R 3 taken together are O-CH 2

R

6 and R 7 are independently CH 2 CHR,, or C(Ris) 2 R, is OH, OR, where R is lower alkyl, or F; R 9 Rio, and R 2 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; is alkyl, aralkyl or aryl; and is C-alkyl, C-aralkyl or C-aryl; WO 02/072542 WO 02/72542PCT/US02/07033 16 R4

IDR

6 R13 R2 \7 00 wherein R, and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR 4; R 2 is selected from the group consisting of 0, S, NH or NR ,;R 3 is N;

R

6 and R 7 are independently CH 2

CHR

5 -or C(R, 5 2 R. is OH, OR, where R. is lower alkyl, or F; R9, RIO, RI, and R 1 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, RU 3 is alkyl, aralkyl. or aryl; R,4 is C-alkyl, C-aralkyl or C-aryl; R, is lower alkyl; and R,, 6 is C-alkyl, C-aralkyl, or C-aryl; R R 5 R 6 R 9 R i o R 1

R

1 2 i wherein R, and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR 1 4 R2 is N; R 3 is selected from the group consisting of 0, S, NH and NR 15; R 5

R

6 and R 7 are independently CH 2

CHR,

5 or C(R, 5 2 R, is OH, OR, where R is lower alkyl, or F; R 9 Rio, R, I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; R 1 4 is C-alkyl, C-aralkyl or C-aryl, is lower alkyl; and R(16 is C-alkyl, C-aralkyl, or C-aryl; WO 02/072542 WO 02/72542PCT/US02/07033 17 R4 9

CKI

N- NO0 (CH& r 00 wherein R 2

R

3

R

4 and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR, 1 and where R 2 and R 3 taken together are O-CH 2

R

6 and R, are independently CH 2

CHR,

5 or C(R, 5 2 is OH, OR, where R is lower alkyl, or F;

R

9 9 Rio) RI, and are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, RD 3 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl, and is lower alkyl; and n=1-3; R 5R 9

R

10 el hrenRl 4 n R 5 ar ineednl eete omtegopcossigo

,F

)re R~ and R, are independently selected frm the group consisting of H, F,l Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; R, 5 is lower alkyl; R, 6 is C-alkyl, Caralkyl or C-aryl; and n=1 -3; WO 02/072542 PCT/US02/07033 00 0 18 012 R 3 o1 00 0 wherein R 4 and R, are independently selected form the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is N; R3 is O, S, NH or R 6 and R, are independently CH 2 CHR,, or R, is OH, OR, where R is lower alkyl, or F;

R

9

RI

0 RI, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R,3 is alkyl, aralkyl or aryl; is lower alkyl; R,6 is C-alkyl, Caralkyl or C-aryl; and n=1-3; R4 R R5 CH2) R9 H

R

13 R1 R 6 R7 R

H

R12 R11 wherein R 2

R

3

R

4 and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and where R2 and R 3 taken together are

O-CH

2

R

6 and R, are independently CH 2 CHR,, or 2 R, is OH, OR, where R is lower alkyl, or F; R,o, R, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl, R 3 is alkyl, aralkyl or aryl; is lower alkyl; and n=1-3; WO 02/072542 WO 02/72542PCT/US02/07033 00 1 R 1 R5K R 7 Rio H

(CH

2 n 1 i 00 wherein R.

4 and R, are independently selected form the group consisting of H, F, Cl, Br, I and OR where Ris lower alkyl; (2 is 0, S, NH or NR, 5

R

3 is N;RP 6 and 1( are independently CH 2

CHR,

5 or C(R 15 2 R, is OH, OR, where R is lower alkyl, or F; Rio, R, and R,2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; is lower alkyl; R,6 is C-alkyl, Caralkyl or C-aryl; R 16 is C-alkyl, C-aralkyl or C-aryl; and n=1l-3; R4 0

R

16 H\ H

_-R

13 H

S

Ri R 6 7 R 8 /H

(CH

2 )n 1 1 wherein R 1 R, and R, are independently selected form the group consisting of H, F, Cl, Br, I and or where R is lower alkyl; R 2 is N; R.

3 is 0, S, NH or NR, 5

R,

6 and R 7 are independently CH 2 CHR, or C(R 1 5 2 is OH, OR, where R is lower alkyl, or F; R9, Rio) R, and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; R, 1 5 is lower alkyl; R 1 6 is C-alkyl, Caralkyl or C-aryl, and n=1-3; WO 02/072542 PCT/US02/07033 00 0

S

R4 ND R R 9 .R io R2- R5

R

k "N R 1 R6 R6' R7 Ra 00 N R12 Rll 0 wherein R, is selected from the group consisting of O, S, NH and R 2

R

3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 5 is H; R 6 and R' are independently H or F; R, is H, lower alkyl,

CH

2 Ar, CH 2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; Ro, and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R,3 is alkyl, aralkyl or aryl; and is lower alkyl; R3 R R s R7 R 7 R Rio R RR8

H

R12 R11 wherein R, is selected from the group consisting of O, S, NH and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and R, and R 3 taken together are O-CH 2

R

4

R

5 and R 6 are independently C-I 2 CHR,, or 2 R, is H, R 8 is OH, OR, where R is lower alkyl, or F; R 9 Ri, RI and R,, 2 are independently selected from the group consisting of H, F, Cl, Br, 1 and lower alkyl; is alkyl, aralkyl or aryl; and is lower alkyl; WO 02/072542 WOO~f72542PCTIUSO2/07033 21 Ct R3 /N R 4

RR

1 Rio N- R J R 5

R

5 R1-v N

NO

R6 R 1 R

H

00 wherein R, is selected from the group consisting of 0, S, NH and NR,; R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and R 2 and R 3 taken together are O-CH 2

R

4 is N; R, is H; R 6 and 6 are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2

CH

2 Ar, CH 2 CHFAr or

CH

2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6di fluorophenyl, 2,3 ,4-tri fluorophenyl, or 2,3 ,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R9, Rio, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and R,, is lower alkyl; R N4 R1 R t. I

\I

wherein R, and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 3 is selected from the group consisting of 0, S, NH and NR, 5 R, is N; R, is H; R 6 and are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3 -fluorophenyl, 4-fl uorophenyl, 2,6-difluorophenyl, 2,3 ,4-tri fluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R. is OH, OR, where R is lower alkyl, or F; R 9 RIO, R, I and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; and is lower alkyl; WO 02/072542 PCT/US02/07033 O 22

OO

R1 3 2 R 5 R 5 V 13 R6 R 6

R

7 R8

H

O R 12

R

11 00 wherein R, is selected from the group consisting of O, S, NH and NR15; R 2 is N; R 3 Oand R 4 are is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 5 is H, R 6 and R' are independently H or F; R, is H, lower alkyl, CH2Ar,

CH

2

CH

2 Ar, CHCHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; Rio, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; and is lower alkyl; R3 R R 7

R

7 R9 Rio 0 R X R13 Ri R R8

H

R12 R11 wherein R, is selected from the group consisting of O, S, NH and R 2 is N; R 3 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl;

R

4 R, and R 6 are independently CH 2 CHR,, or 2 R, is H; R, is OH, OR, where R is lower alkyl, or F; RI 0 and are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R, 3 is alkyl, aralkyl or aryl; and R 5 is lower alkyl; WO 02/072542 WO 02/72542PCT/US02/07033 00 23 R3 2 R 5

R

5 1 R 0

R

6

R

6

R

7

R

8 H

R

1 2 Ril 00 wherein R, is selected from the group consisting of 0, S, NH and R 3 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 2 and R 4 are N; R, is H; R.

6 and R 6 are independently H or F; (7 is H, lower alkyl, CH 2 Ar,

CH

2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3 ,4-trifluorophenyl, or 2,3,4,5,6pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; P.9, RIO, R, I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and is lower alkyl;

R,,R

9

R

10 q R 4 RlN

N\/

R

6

R

6 K

R

8 /H wherein R, is selected from the group consisting of 0, S, NH and R, is selected from the group consisting of H, F, Cl, Br, I and Or where R is lower alkyl; R 3 and R 4 are N; R5 is H; and R, 6 are independently H or F; R(7 is H, lower alkyl, CH 2 Ar,

CH

2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3 ,4-trifluorophenyl, or 2,3,4,5,6pentafluorophenyl;

R

8 is OH, OR, where R is lower alkyl, or F; Rq, RIO, R, I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; RD 3 is alkyl, aralkyl or aryl; and is lower alkyl; WO 02/072542 PCT/US02/07033

R

6 R6' wherein R, is selected from a group consisting of O, S, NH or R 2

R

3 and R 4 are N; R 5 is H, R 6 and R' are independently H or F; R 7 is selected from the group consisting of H, lower alkyl, CH2Ar, CH 2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 RIo, and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R,3 is alkyl, aralkyl or aryl; and is lower alkyl; wherein R, and R 3 are independently selected from the group consisting of O, S, NH and R 2

R

2 and R 4 are independently selected from the group consisting of H, F, CI, Br, I and OR where R is lower alkyl; R, is H; R 6 and are independently H or F;

R

7 is H, lower alkyl, CH 2 Ar, CHCHAr, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4- WO 02/072542 PCT/US02/07033 trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 Ro, and are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R 1 3 is alkyl, aralkyl or aryl; and R, 5 is lower alkyl; wherein R, and R 2 are independently selected from the group consisting of O, S, NH and NR 1 R2', R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is H; R 6 and R 6 are independently H or F;

R

7 is H, lower alkyl, CHAr, CH 2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R 8 is OH, OR, where R is lower alkyl, or F; R, Rio, R and R,2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; and R, 5 is lower alkyl; R/C R R9

R

10 0 R1 wherein R, and R 4 are independently selected from the group consisting of O, S, NH and R 2 and R 3 are independently selected from the group consisting of H, F, Cl, WO 02/072542 WO 02/72542PCT/US02/07033 26 NI Br, I and OR where RW4 and R 2 and R 3 taken together are O-CH 2 R5, &6 and (7 are Ct independently CH4 2

CHR,

5 or C(R, 5 2

R

8 is OH, OR, where R is lower alkyl, or F; R 9 RIO, R, and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; R,4 is C-alkyl, C-aralkyl or C-aryl and R,, is lower alkyl; 00R

/R

1

S

R

8

H

wherein R, and R 2 are independently selected from the group consisting of 0, S, NH and NR 1 5 R27', R 3 and (4 are independently selected from the group consisting of H, F, CI, Br, Iand OR 14 and R(3 and R(4 taken together are O-CH 2

R

5 R6 and Rtare independently CH 2 CHR,, or C(R, 5 2 R, is OH, OR, where R is lower alkyl, or F; Rq,

R

1 ,)RII and R32 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl, and is lower alkyl; WO 02/072542 PCT/US02/07033 0 27

O

wherein R 2

R

3 and R 4 are independently selected from the group consisting of H, SF, Cl, Br, I and OR where R is lower alkyl; and where R, and R 2 taken together are 0- I CH 2 R, is H, R 6 and R 6 are independently H or F; R 7 is H or lower alkyl, CH 2 Ar,

CH

2

CH

2 Ar, CH 2 CHFAr or CH 2

CF

2 Ar, where Ar is aryl, 2-fluorophenyl, 3fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6pentafluorophenyl; Rg is OH, OR, where R is lower alkyl, or F; RiO, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower 0O alkyl; R, 3 is alkyl, aralkyl or aryl; Rs is lower alkyl; and X, is C-R 3 or N; X2 is C-R 4 0or N; and X3 is C-R 4 or N; Ri xiR

R

6

R

9 Rio xlI 1 3 1 R 7 N

O

R

8

H

R12 R11 wherein R 2

R

3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR, 4 and where R, and R2 taken together are O-CH 2

R

6 and R 7 are independently CH 2 CHR,, or 2

R

8 is OH, OR, where R is lower alkyl, or F;

R

9 Ro, and RI 2 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R, 3 is alkyl, aralkyl or aryl; R,4 is C-alkyl, C-aralkyl or C-aryl; R,, is lower alkyl; and X, is C-R 2 or N; X 2 is C-R 3 or N; and X 3 is C-R 4 or N.

Derivatives of the above compounds in which 5-membered rings contain O, S or N heteroatoms and 6-membered rings contain N heteroatoms are also provided herein. and (S)-forms, and racemic mixtures thereof, of the foregoing compounds are also provided herein.

WO 02/072542 WO 02/72542PCTUS02O7033 00 28 Other preferred compounds are those selected from the group consisting of the or Ct forms and racemic mixtures of: 1 -(4-methanesulphonamidepheoxy)3 -(N-methyl-3 ,4-dichlorophenylethylamino)-2propanol; I -(4-Methanesulphonamidephenoxy)-3 ,4-dichlorophenylethyl-amino)- 2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 -(N-ethyl-3 ,4-dichloro-phenylethylamino)-2propanol; 001 -(4-Methanesulphonamnidephenoxy)3 -(N-propyl-3 ,4-dichloro-phenylethylamino)-2propanol; 1 4 -Methanesulphonamidephenoxy).3 -(N-butyl-3 ,4-dichloro-phenylethylamino)-2propanol; I 4 -Methanesulphonamnidephenoxy)-3-(N..benzyl.3 ,4-dichloro-phenylethylamino)-2propanol; I -(4-Methanesulphonamidephenoxy)-3-(N-(2-fluorobenzyl)-3 ,4-dichlorophenylethylamino)-2-propanol; 1 4 -Methanesuphonaidephenoxy)3(N(3-fluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol; I -(4-Methanesulphonamidephenoxy)-3 -(N-(3-fluorobenzyl)-3 ,4-dichlorophenylethylamino)-2-propanol; I 4 -Methanesulphonamidephenoxy)-3-(N(2,6-difluorobenzyl)-3 ,4-dichlorophenylethylamino)-2-propanol; I -(4-Methanesulphonamidephenoxy)-3 ,4-trifluorobenzyl)-3 ,4-dichlorophenyl -ethylamino)-2-propanol; I -(4-Methanesulphonamidephenoxy)-3-.(N-(2,3 ,4,5 ,6-pentafluoro-benzyl)-3 ,4-dichlor ophenylethylamino)-2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 -hydroxyethyl)-3 ,4 -di chilorophenylethylamino)-2-propanol; 1 -(3-Methanesulphonamidephenoxy)3 4 -dichlorophenylethyl-ami no)-2-propanol; 1 2 -Methanesulphonamnidephenoxy)-3 4 -d ichlorophenyl -ethyl amino)-2-propanol; 1 4 -Methanesulphonamidophenoxy)-3 -(N-acetyl-3 ,4-dichloro-phenylethylamino)-2.

propyl acetate; WO 02/072542 PCT/USO2/07033 00 29 29 SN-(3, 4 -dichlorophenyl)ethyl-5-(4-methanesulphonamidophenoxy)methyl-oxazolidine- 2-one; 1 -(4-N-methyl-methanesulphonamidephenoxy)-3-(3,4-dichloro-phenylethylamino)-2- N propanol; 1 -(4-benzenesulphonamidophenoxy)-3-(3,4-dichloro-phenylethyl-amino)-2propanol; 1-(4-Nitrophenoxy)3-(3, 4 -dichlorophenylethylamino)-2-propanol; mixtures thereof and pharmaceutically acceptable salts thereof.

This invention also provides a method of treating neurodegeneration associated with a pathological condition characterized by lowered brain-tissue pH, said method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brain-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of the above-described compounds.

The methods of this invention also include treating neurodegeneration associated with a pathological condition characterized by lowered brain-tissue pH, said method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brain-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of: zolantidine dimaleate; 2 4 -chloroanilino)-4-(4-phenylpiperazino)cyclopent-2-en- I1-one; haloperidol; cirazoline; 1,10-phenanthroline; 6-[2-(4-imidazolyl)ethylamino]-N-(4trifluoromethylphenyl)heptanecarboxamide; I -(4-methanesulfonamidophenoxy)-3-(Nmethyl-3,4-dichlorophenylethylamine)-2-propanol hydrochloride (AM92016, compound 93); 3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-l H-pyrrolo[2,3-b]pyridine; benzodiaxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione; (+)-8-hydroxy-2dipropylaminotetralin hydrobromide; (+)-7-hydroxy-2-dipropylaminotetralin hydrobromide; 8-[3-(4-fluorophenoxy)propyl]- 1-phenyl-1 ,3,8-triazospiro[4.5]-decan-4-one (AMI 193); PPHT; 4 4 -fluorobenzoyl)-1-(4-phenylbutyl)piperidine; 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI); benextramine; trifluoperidol; clobenpropit; and benoxathian.

WO 02/072542 PCT/US02/07033 This invention also provides a method of treating neurodegeneration associated with a pathological condition characterized by lowered brain-tissue pH, said method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brain-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of or enantiomers or mixtures thereof of compounds of the formula:

A-B-

wherein one of R 9 Rio, RI2 and is 0 O S.R13 where R,3 is alkyl, aralkyl or aryl; where R, 7 is H or lower alkyl; and the others of R, 2 and are H, F, Cl, I or R wherein R is lower alkyl; or:

A-B-

WO 02/072542 PCT/US02/07033 31 wherein R 0 i, and R 12 are independently selected from the group consisting of H, F, Cl, Br, I, and R wherein R is lower alkyl, and R 1 3 is alkyl aralkyl or aryl; wherein A is a bulky, ring-containing group; and wherein B is selected from the group consisting of: H H F b R7 R8 wherein R, and R 6 are independently H or F; and R 7 is H, lower n-alkyl, CH 2 Ar,

CH

2

CH

2 Ar, CH 2 CHFAr, or CH 2

CHF

2 Ar; and R 8 is OH, OR, where R is lower alkyl, or F;

HH

R

6 R wherein R 6 and R 6 are independently H or F; R, is CH 2 and R, is O; wherein R 6 and R 7 are independently CH 2 CHR or CR2 where R is lower alkyl; and R, is OH, OR, where R is lower alkyl, or F; WO 02/072542 PCT/US02/07033 S32

HH

R

R7 R8

(CH

S w wherein R 6 and R, are independently CH 2 CHR or CR, where R is lower alkyl; and R, is OH, OR, where R is lower alkyl, or F; 00 (CH2)n 0• H H RG R7 R8 wherein R, and R, are independently CH 2 CHR or CR 2 where R is lower alkyl; R, is OH, OR, where R is lower alkyl, or F; and n=1-3; and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.

The novel compounds disclosed herein may be used to treat pathological conditions not involving lowered brain-tissue pH, as well as pathological conditions involved lowered pH. Such conditions include Parkison's Disease, Alzheimers, and Amyotrophic Lateral Sclerosis (ALS).

This invention also provides methods of making compounds described herein comprising: the or form of a compound having the formula: C1 I O-R2 R3 CI YA O WO 02/072542 PCT/US02/07033 0 33

O

N wherein R, is CH 3 or H, R 2 is H, and R 3 is selected from the group consisting of NHSO 2

CH

3

N(CH

3

)SO

2

CH

3

NHSO

2 Ph and NO 2 said method comprising reacting an or (R)-glycidyl IN (R)-R 3 -phenyl ether with N-methyl-3,4-dichlorophenylethylamine.to form the compound wherein R, is CH 3 or with 3,4-dichlorophenylethylamine to form the compound of the above formula wherein R, is H.

This invention also comprises a method of forming a further compound of said OO formula wherein R, is selected from the group consisting of C 2

H

5 C3H 7

C

4

H

9 benzyl, 2- Sfluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluorobenzyl, and 2,3,4-trifluorobenzyl, said method comprising reacting the product of the foregoing method wherein R, is H with 1,2 dichloroethane to form said further compound.

A further method is provided for forming a further compound of said formula wherein R, is C 2

H

4 -OH, wherein said method further comprises reacting a product of the above formula wherein R, is H with O-butyryl glycoaldehyde to give a second reaction product; and further reacting said second reaction product with sodium methoxide to form said further compound.

A further method is provided of forming a further compound of said formula wherein R, is acetyl comprising reacting the compound of the above formula wherein R, is H with N,N-dimethylaminopyridine and acetic anhydride.

A further method is provided further comprising forming a further compound of said formula wherein R, and R 2 taken together are CH 2

-O-CH

2 comprising reacting the compound of the above formula wherein R, is H with l,1'-carbonyldiimidazole and N,Ndimethylaminopyridine in benzene.

R3 may be a meta- or para-substituent in the reaction intermediates and in the final product. Intermediates and corresponding final products may be in the or (R)-forms.

WO 02/072542 PTUO/73 PCT/US02/07033 34 A method is also provided for making or 1 methanesulphonamidephenoxy)-3-(3 4 -dichlorophenylethylamino)-2-propanol) comprising the steps of:

IND

reacting 2-nitrophenol with or (R)-glycidyl nosylate to form or glycidyl o-nitrophenyl ether; reacting the product of step with 3,4-dichioropentylethylamine to formn (S) or (R)-1I-(2-nitrophenyoxy)-3 4 -dichlorophenylethylamino)-2-propanol; reacting the product of step with p-tolune-sulphonic acid and benzaldehyde to form 2-phenyl-3 (N-phenylethylamino)-5 -(4-nitrophenoxy methyl)oxazol idine; reacting the product of step with sodium hydroxide to form 2-phenyl-3(Nphenyl ethyl ami no)-5 -(4-am inophenoxy methyl)oxazolidine; and reacting the product of step with diisopropylamine and methansulfonylchloride to form 1 -(2-methanesulphoneamidephenoxy)-3-(3 ,4dichlorophenylethylamino)-2-propanol.

A method is also provided for making or (R)-1I-(4-N-methylmethanesulphonamidephenoxy)-3 4 -dichlorophenylethylamino)-2-propanoI comprising: reacting or (R)-blycidyl N-methylsulfonyl-p-aminophenyl ether with potassium carbonate and methyl iodide to form or (R)-glycidyl N-methyl- N-methanesulfonyl-p-aminophenyl ether; reacting the product of step a) with 3,4-dichiorophenylethylamine to form or I 4 -N-methyl-methanesulphonamidephenoxy)-3-(3 ,4di chlorophenyl ethyl am ino)-2-propanol.

WO 02/072542 WO 02/72542PCT/USO2/07033 N A method is also provided for making or benzenesulphonamideophenoxy)-3 ,4-dichloro-phenylethylamino)-2-propano comprising INO reacting or (R)-glycidyl N-methylsulfonyl-aminophenyl ether with N,N-diisopropyl-Nethylamine to form or (R)-glycidyl N-benzenesulfonyl-p-aminophenyl ether, and reacting said ether with 3,4-dichiorophenylethylamine to form said or benzenesulphonamideophenoxy)-3 ,4-dichloro-phenylethylami no)-2-propanol.

A method is also provided for making or (R)-1-(4-nitrophenoxy)3-(3,4dichlorophenylethylamino)-2-propanol comprising reacting p-nitrophenyl ether with 3,4dichirophenylethylamnine to formn said or 1 -(4-nitrophenoxy)3-(3,4dichlorophenylethylamino)-2-propanol.

The remaining NMDA-receptor blockers which are derivatives of and related compounds to those described above may be synthesized, as will be appreciated by those of skill in the art, by methods analogous to those described herein.

DETAILED DESCRIPTION The term "alkyl" takes its usual meaning in the art and is intended to include straight-chain, branched and cycloalkyl groups. The termn includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, 2-methylbutyl, I -methylbutyl, I -ethylpropyl, 1, 1 -dimethyipropyl, n-hexyl, 1 -methylpentyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 3,3 -dimethylbutyl, 2,2-dimethylbutyl, 1,1 -dimethylbutyl, 2-ethylbutyl, I -ethylbutyl, 1 ,3-dimethylbutyl, n-heptyl, 4-methylhexyl, 3 -methylhexyl, 2-methylhexyl, 1 -methylhexyl, 3 -ethylpentyl, 2-ethylpentyl, 1 -ethylpentyl, 4,4-di methylpentyJ, 3,3 -dimethylpentyl, 2,2-dimethylpentyl, I1, I -dimethylpentyl, n-octyl, 6-methylheptyl, 5 -methylheptyl, 4-methylheptyl, 3 -methylheptyl, 2-methylheptyl, 1 -methylheptyl, I -ethylhexyl, 1 -propylpentyl, 3-ethylhexyl, 4,4-dimethylhexyl, 2,2-di ethyl butyl, 3 ,3-diethylbutyl, and 1 -methyl- I -propylbutyl. Alkyl groups are optionally substituted. Lower alkyl groups include among others methyl, ethyl, n-propyl, and isoprophyl groups. Lower alkyl groups as referred to herein have one to six carbon atoms.

WO 02/072542 PCT/US02/07033 00 0o 36 SThe term "bulky ring-containing group" refers to a group containing I or more ring structures which may be aryl rings or cycloalkyl rings.

(N

The term "cycloalkyl" refers to alkyl groups having a hydrocarbon ring, particularly to r those having rings of 3 to 7 carbon atoms. Cycloalky groups include those with alkyl group substitution on the ring. Cycloalkyl groups can include straight-chain and branched-chain N portions. Cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl. Cycloalkyl groups can

C

N optionally be substituted.

The term "aryl" is used herein generally to refer to aromatic groups which have at least one ring having a conjugated pi electron system and includes without limitation carbocyclic aryl, aralkyl, heterocyclic aryl, biaryl groups and heterocyclic biaryl, all of which can be optionally substituted. Preferred aryl groups have one or two aromatic rings.

Substitution of alkyl groups includes substitution at one or more carbons in the group by moieties containing heteroatoms. Suitable substituents for these groups include but are not limited to OH, SH, NH2, COH, CO 2 H, ORc, SRc, NRc Rd, CONRc Rd, and halogens, particularly fluorines where Rc and Rd, independently, are alkyl, unsaturated alkyl or aryl groups. Preferred alkyl and unsaturated alkyl groups are lower alkyl, alkenyl or alkynyl groups having from I to about 3 carbon atoms.

"Aralkyl" refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include among others benzyl, phenethyl and picolyl, and may be optionally substituted. Aralkyl groups include those with heterocyclic and carbocyclic aromatic moieties.

"Heterocyclic aryl groups" refers to groups having at least one heterocyclic aromatic ring with from I to 3 heteroatoms in the ring, the remainder being carbon atoms. Suitable heteroatoms include without limitation oxygen, sulfur, and nitrogen. Heterocyclic aryl groups WO 02/072542 PCT/US02/07033 O37 CN include among others furanyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolo, pyrimidyl, pyrazinyl,

M

c imidazolyl, benzofuranyl, quinolinyl, and indolyl, all optionally substituted.

Cl "Heterocyclic biaryl" refers to heterocyclic aryls in which a phenyl group is substituted by a heterocyclic aryl group ortho, meta or para to the point of attachment of the phenyl ring to the decalin or cyclohexane. Para or meta substitution is preferred.

Heterocyclic biaryl includes among others groups which have a phenyl group substituted with I a heterocyclic aromatic ring. The aromatic rings in the heterocyclic biaryl group can be optionally substituted.

"Biaryl" refers to carbocyclic aryl groups in which a phenyl group is substituted by a carbocyclic aryl group ortho, meta or para to the point of attachment of the phenyl ring to the decalin or cyclohexane. Biaryl groups include among others a first phenyl group substituted with a second phenyl ring ortho, meta or para to the point of attachment of the first phenyl ring to the decalin or cyclohexane structure. Para substitution is preferred. The aromatic rings in the biaryl group can be optionally substituted.

Aryl group substitution includes substitutions by non-aryl groups (excluding H) at one or more carbons or where possible at one or more heteroatoms in aromatic rings in the aryl group. Unsubstituted aryl, in contrast, refers to aryl groups in which the aromatic ring carbons are all substituted with H, e.g. unsubstituted phenyl 6 or naphthyl H 7 Suitable substituents for aryl groups include among others alkyl groups, unsaturated alkyl groups, halogens, OH, SH, NH2, COH, CO 2 H, ORe, SRe, NRe Rf, CONRe Rf, where Re and Rf independently are alkyl, unsaturated alkyl or aryl groups. Preferred substituents are OH, SH, ORe, and SRe where Re is a lower alkyl, i.e. an alkyl group having from 1 to about 3 carbon atoms. Other preferred substituents are halogens, more preferably fluorine, and lower alkyl and unsaturated lower alkyl groups having from 1 to about 3 carbon atoms. Substituents include bridging groups between aromatic rings in the aryl group, such as CO 2

CO--,

CHCH-- and (CH 2 )I where I is an integer from 1 to about 5, and particularly CH 2 Examples of aryl groups having bridging substituents include phenylbenzoate, Substituents also include moieties, such as (CH 2

O--(CH

2 or WO 02/072542 PCT/US02/07033 0 38 I OCO--(CH 21 where I is an integer from about 2 to 7, as appropriate for the moiety, which S bridge two ring atoms in a single aromatic ring as, for example, in a 1, 2, 3, 4-tetrahydronaphthalene group. Alkyl and unsaturated alkyl substituents of aryl groups can in turn optionally be substituted as described supra for substituted alkyl and unsaturated alkyl groups.

C",

The compounds of Formula I and their salts, as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application 00 with the usual pharmaceutical adjuvant materials, for example, organic or inorganic inert carrier materials, such as, water, gelatin, lactose starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols and the like. Carriers which do not consist of water or water and buffer alone are also contemplated in this invention. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances. Thus part of this invention is a pharmaceutical composition comprising a compound of Formula I, in particular a preferred compound as described above, or a pharmaceutically acceptable salt thereof and an inert carrier.

The dosage of the compounds referred to herein can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in the range of about 0.1 mg per dosage to about 1000 mg per day of a compound of formula I although the upper limit can also be exceeded when this is shown to be indicated. An amount effective to alleviate the neurodegeneration depends on the individual, however alleviation occurs when the condition in question exhibits either symptomatic improvement or improvement according to an accepted assay. For the compounds herein having enhanced activity at pH lower than normal, dosages of these compounds for use in the methods of this invention involving administration to a patient having lower-than-normal brain-tissue pH, are less than normal dosage amounts for similar WO 02/072542 PCT/US02/07033 00 39 CN compounds not having such enhanced activity at lowered pH. When used to treat stroke or t other traumatic ischemic events, the treatment should be administered prior or to or immediately after the event.

(N

Lowered pH due to pathological conditions is between about 6.4 and about 7.2, generally about 6.9. Normal brain-tissue pH is between about 7.2 and about 7.6, generally about 7.4.

00

EXAMPLES

The following examples illustrate the present invention in more detail. However, they C N are not intended to limit its scope in any manner.

Example 1: NMDA receptor block in Xenopus oocytes by novel compounds Current recordings were obtained using two electrode voltage clamp of Xenopus oocytes injected with cRNA encoding the NRI-la and NR2B NMDA receptor subunits.

Cells were injected with 5-15 ng of cRNA encoding NRI-la in combination with a 2-3 fold greater amount of either NR2B cRNA. Injected oocytes were maintained at 17°C in Barths solution containing penicillin (10 U/ml) and streptomycin (10 pg/ml) for 2-6 days, after which recordings were made at room temperature from oocytes continuously perfused in a standard frog Ringers solution. This solution was composed of(in mM): 90 NaC1, 1.0 KCI, Hepes and 0.5 BaCI 2 Recording pipettes were filled with 0.3M KCI. Saturating concentrations of glutamate (20-50 pM) and glycine (20 pM) were used to activate the receptor. Drugs were prepared daily from frozen stock solutions in DMSO.

Glutamate/glycine-activated currents were typically elicited from a holding potential of-20 to mV. Current signals were digitized and analyzed using custom acquisition software. To study the effects of pH, oocytes were perfused with Ringer's solution at the desired pH until a stable baseline had been reached before subsequent agonist application.

Application of glutamate and glycine produced a stable, rapidly-rising and nondesensitizing current in the majority of oocytes. Oocytes in which the glutamate/glycine current was not stable or in which the baseline holding current drifted were discarded.

Inhibition of the glutamate/glycine current by drugs was examined by applying 1-4 different WO 02/072542 PCT/US02/07033 concentrations of the antagonist to each oocyte. The amplitude of the glutamate/glycine current at each concentration of antagonist was expressed as a percentage of the control glutamate/glycine current in the absence of antagonist, and IC50's were determined by fitting the logistic equation to the data (n=3-46 oocytes per condition). On average recordings were made from 14 oocytes per condition. The fold potency boost was calculated as the ratio of the experimental IC50 values determined at pH 7.6 and 6.9 (1C50 at pH 7.6 IC50 at pH 6.9).

Table A. Novel NMDA receptor inhibitors with potency boosts 5-fold for changes from pH 7.6 to pH 6.9 0

S

'4 Racemic mixtures were studied when stereochemistry is not indicated. The folddecrease in IC50 as a function of pH for antagonists ofNRl-la/NR2B receptors was measured in Xenopus oocytes as described above. All compounds were more potent at pH 6.9.

I

Novel Compounds 93-31 (S) 93-29 (S) 93-24 93-1 (R) 93-8 (S) 93-28 (S) 93-5 (S) 93-30 (S) 93-6 (S) 93-2 (S) Known compounds Haloperidol R1 R2 R3 R4 R5 n-butyl

H

.H

Methyl EtOH

COCH

3 Ethyl benzyl n-propyl Methyl

OH

OH

OH

OH

OH

OCOCH

3

OH

OH

OH

OH

Me phenyl Me Me Me Me Me Me Me Me IC50 at pH 6.9 (pIM) 0.058 1.160 1.360 0.085 0.029 1.638 0.020 0.070 0.111 0.063 Fold increase in potency between pH 7.6 and 6.9 51.2 18.0 11.8 11.3 11.3 11.1 8.00 16.8 6.54 5.87 n nl 1C r S~1 j'J..J WO 02/072542 PCT/US02/07033 41 Table B. Novel NMDA receptor inhibitors with pH potency boosts <5 fold for changes from pH 7.6 to pH- 6.9 C1 Ri -R2 R3 Racemnic mixtures were studied when stereochemnistry is not indicated. The fold decrease in IC50 as a function of pH for antagonists of NRl-IlaNR2B receptors was measured in Xenopus oocytes as described above.

Novel compound at pH 6.9

(P~M)

Fold increase In potency between pH 7.6 and 6.9 93-34 meta-F-benzyl 93-35 ortho-F-benzyl 93-4(S)

H

93-3 H 93-14 H 93-27 (S)0 93-33 para-F-benzyl Known compounds Ifenprodil- Ro256981-

H

H

H

H

H

R1=R2

H

N HSO 2 Me

NHSO

2 Me

NHSO

2 Me

NHSO

2 Me

OCH

3

NHSO

2 Me

NHSO

2 Me 0.2 10 0.048 0.026 0.099 19.900 0.338 0.520 4.62 3.60 3.54 3.26 2.01 0.95 0.810 0.068 2-66 f~ Ala IJAJIU f. A A A WO 02/072542 PCT/US02/07033 42

O

N Table C. Importance of chain N ionization on potency boost at low pH for SNMDA receptor inhibitors.

CI NO I R1 O-R2 00 o All compounds shown are assumed to be novel. Compounds with pKa values for the chain nitrogen between 9 and 5 undergo changes in the concentration of the ionized species over the range ofpH values tested (6.9 Compounds with reduced pKa values show larger increases in ionization at pH 6.9 compared to pH 7.6. We found a significant correlation between the potency boost and pKa of the chain nitrogen for the following series of compounds (n-butyl was omitted because other features of the molecule dominate the potency boost). Molecules with no ionization at this nitrogen showed no pH dependent potency boost.

For each compound, the pKa of the amine group in the linker chain was calculated by the web-based pKa calculator from ACDLabs (www.acdlabs.com). The fold decrease in as a function of pH for antagonist of NRI-la/NR2B receptors was measured in Xenopus oocytes as described above.

WO 02/072542 WO 02/72542PCT/USO2/07033 00 Compounds with ionization of N changing between pH 6.9 and 7.6 93-4 (8) 93-6 (S) 93-5 (S) 93-31 (S) 93-2 (S) 93-8 (S) 93-30 (S) Compound with an unionized nitrogen at both pH 6.9 and 7.6 pKa of the chain amine

H

n-Propyl Ethyl n-Butyl Me EtOH Benzyl 8.36 8.11 8.11 8.11 8.03 7.57 7.08 3.54 6.54 8.00 51.2 5.87 11.3 16.8 Fold increase in potency between pH 7.6 and 6.9 93-27(S) R1=R2 93-7 R=R2<1 0.954 WO 02/072542PT/SO/073 PCT/US02/07033 44 Table D. Importance of the NHSO 2 -Me constituent on the phenyl ring for NMDA receptor inhibitors.

R2 c1 RI R3 K1 All compounds shown are assumed to be novel. Racemic mixtures were studied when stereochemistry is not indicated. Values not determined are indicated as N.D. The fold decrease in 1C50 as a function of pH for antagonists of NRlI-I aNR2B receptors was measured in Xenopus oocytes as described above. All compounds were more potent at pH 6.9.

Compound pH 6.9 Wti) Fold increase in potency between pH 7.6 and 6.9 93-4 (S) 93-9 (S) 93-32 (S) 93-7 (S) 93-29 (S) 93-10(S) 93-14 93-16

H

H

NHSO

2 -Me

H

H-

H-

H-

H

H

NHSO

2 -Me

H

H

ifI

H-

H

H

NHSO

2 -Me

H

HI

N(CI-1 3 S0 2 -Me

NHSO

2 -phenyl

NO

2

OCH

3

OCF

3 0.026 0.208 17.9 2.33 1.16 12.1 19.9 11.2 3.54 8.19

N.D.

5.51 18.02 1.60 2.01 4.82

I

WO 02/072542PC/S2173 PCT/US02/07033 Table E. Anticonvulsant effect Drug Vehicle Carbamnazelpin e 93 93 93 93 93-4 93-4 93-4 93-4 93-8 93-8 93-8 93-27 93-27 __93-27 Dose (mglkg) 0 40 10 10 10 30 3 3 30 30 30 30 30 30 30 30 Delay from drug injection to electroshock (min) 15 30 15 30 60 240 15 60 15 60 15 30 60 15 30 60 Control tonic hindlimb extension (THE) time (sec) 8.5 +0.3 8.5 +0.3 8.5 +0.4 8.8 +0.2 9.0 +0.2 7.4 +0.3 7.2 +0.2 6.7 +0.6 7.5 +0.2 6.6 +0.6 7.0 +0.4 7.4 +0.2 7.7 +0.4 7.4 +0.31 8.1 0.5 7.5 +0.2 THE in drug control) 102 +3.1 0.0 +0.0 78.2 58.5 11.3 62.4 3.9* 96.2 +1.7 91.1 +2.7 109 +11.5 66.6 12.5* 30.8 12.1* 91.9 +0.4 85.7 +2.8 59.3 4.1 97.0 +0.6 95.6 +1.3 89.7+0.8 Anticonvulsive effects of 1 -(4-methanesulfonamidophenoxy)-3 -(N-methyl-3 ,4dichlorophenylethylamine)-2-propanol hydrochloride (AM920 16) [Compound 93], 1 methanesul fonamideophenoxy)-3 ,4-dichlorophenylethylamine)-2-propanol hydrochloride (Compound 93-4] and I -(4-methanesulphonamidephenoxy)-e-(N-(2-hydroxyethyl)-3 ,4dichlorophenylethylamino)-2-propanol [Compound 93-8], but not methanesulphonamideophenoxy)-3 -(N-acetyl-3 ,4-di chiorophenylethyl amino)-2-propyl acetate [compound 93-27] were shown.

Methods: Male Sprague-Dawley rats weighing less than 150 gm were used for these experiments. Maximal electroshock seizures were produced by delivering 200 ms biphasic WO 02/072542 PCT/US02/07033 0 46 C, square-wave pulses of 200 mA at 60 Hz via corneal electrodes, using a Wahlquist Constant t Current Source (Salt Lake City, UT). A drop of 0.9% lidocaine in saline was applied to each cornea 30 s before stimulus delivery to minimize pain. Automatic timers recorded the S durations of tonic hindlimb flexion, tonic hindlimb extension (THE), clonus and flaccidity that sequentially followed stimulus delivery. The duration of THE was used as an index of seizure severity. Animals were stimulated on three consecutive days, referred to as "control", S"test", and "recovery". A minimum control THE duration of 4 s was used as a criterion for Q inclusion in subsequent testing; 90% of animals screened had a control THE duration greater Sthan 4 s. On "test" day, each animal received either vehicle or drug at varying intervals prior to stimulation. Reversibility of drug effect on THE was ascertained by response to stimulation administered one day after the "test" session. The values shown in the table are the mean sem) THE duration in the test condition, as a percentage of the mean of control and recovery conditions. Four rats were used for each time point.

P 0.001 for difference from vehicle by one-way ANOVA with Dunnett's post hoc test.

For all other conditions P 0.05.

Example 2: Synthetic Methods Compounds implied by the following general formula and given in Table 1 are representative.

Cl CO-R2 R3 RC H Ri H WO 02/072542PCISIO73 PCTIUS02/07033 00 00 47 Table 1 Compound R____R2__R3 4

CH

3 H 4-NHSO 2

CH

3 H- H 4-NHSO 2

CH

3 6 CAH H 4-NHSO 2

CH

3 7 C 2 H1 4 -OH H 4-NHSO 2

CH

3 8

C

3 1- 7 H 4-NHSO 2

CH

3 9

C

4 11 9 H 4-NHSO 2

CH

3 Benzyl H 4-NHSO 2

CH

3 I1I 2-Fluorobenzyl H 4-NHSO 2

CH

3 12 3-Fluorobenzyl H 4-NHSO 2

CH

3 13 4-Fluorobenzyl H 4-NHSO 2

CH

3 14 2,6-Dif'Iuorobenzyl H 4-NHSO 2

CH

3 2,3,4-Trifluorobenzyl H 4-NHSO 2 CH3 16 H H 3-NHSO 2

CH

3 17 H H 2-NHSO2CH 3 18 acetyl acetyl 4-NHSO 2

CH

3 19 RIR=4-NHSO 2

CH

3 H H 4.-N(CH 3

)SO

2

CH

3 21 H H 4-NHSO 2 Ph 22 H H- 4-NO 2 Synthesis of the above series is exemplified by 4 and 5 as shown in Scheme 1.

WO 02/072542 WO 02/72542PCT/US02/07033 48 SCHEME I

OH

0 2 NJC: GsF /DMF N.r

H

O2N

HH

THF Pc'C(en) CH 3

-SO

2 CI 0.

H

H C- CH(CH 3 2 H 2

N

H2-

CH(CH

3 )A 2 Cl

NH

Kl

HO

Cl0~ NHSO 2 CH 3 R H 4 R=CH 3

R=H

Spectroscopic and Purity Determinations. The 'H-NMR and 3 C-NMR spectra were recorded on a Varian Inova-400 (400MHz) spectrometer. HPLC analyses were performed on a Schimadzu LC-IOA system equipped with a SPD-IOA UV detector. Enantiomeric excesses were determined by HPLC on a Chiralcel GD column using a Hexane-ethanol 90: 10 solvent system. Hydrogenations were performed using the baloon technique in a two-necked flask.

WO 02/072542 PCT/US02/07033 O 49

O

Syntheses: All the reactions were performed under anhydrous nitrogen atmosphere in ovendried glassware.

Preparation of (S)-Glycidyl p-Nitrophenyl Ether S p-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room S temperature and (S)-Glycidyl nosylate (1.71 g, 6.6 mmol) was added. The system was stirred OO for an additional 24 hours at room temperature. Water (150 ml) was added, and the solution 0 was extracted with ethylacetate. The organic phase was dried over MgSO 4 and evaporated.

The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent system to give (S)-Glycidyl p-nitrophenyl ether (99.6% ee, based on chiral HPLC with Chiralcel OD, m.p 78-9 0 C) as a yellowish solid (1.21 g, 93% yield). The NMR values are the same as the literature values for the racemic mixture: 'H-NMR (CDCI) 8 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H), 4.38 (dd, 1H), 6.99 (dd, 2H), 8.2 (dd, 2H).

The (R)-enantiomer of compound 1, starting with (R)-Glycidyl nosylate was prepared similarly: 'H-NMR (CDCI 3 82.79 (dd, 1H), 2.95 (t 1H), 3.4 (m 1H), 4.0 (dd, 1H), 4.39 (dd, 1H), 7.00 (dd, 2H), 8.2 (dd, 2H).

Preparation of Palladium-on-carbon ethylenediamine complex as a reducing agent.

Palladium on activated carbon w/w, 0.2 g) was tared in a three-necked baloon flask. Then, ethylenediamine (0.42 g, 0.1 M) in 70 ml anhydrous methanol was added to the Pd/C under an argon atmosphere. The reaction mixture was stirred for 32 hours under argon. The catalyst was filtered and washed with methanol and ether, then dried for 24 hours under high vacuum pumping.

Preparation of (S)-Glycidyl p-Aminophenyl Ether (2-S.

Compound 1 (0.5 g, 2.6 mmol) and 5% Pd/C(en) (10% of the weight of starting material) in ml anhydrous THF was hydrogenated at ambient pressure and temperature for 3-5 hours. The reaction mixture was filtered through a membrane filter (13, 0.22 tim) and the filtrate was concentrated in vacuo. The compound was obtained as a crude mixture of products arising WO 02/072542 PCT/US02/07033 00 O from nitro group reduction and epoxide ring opening. Isolation of the desired compound was difficult because of the lability of the components of the mixture on silica gel. The product N ratio from NO 2 reduction and ring opening (94:6) was determined by integrating the epoxidering protons in the reduced compound and the methyl proton in the ring opened compound (98% total yield for the mixture). The NMR signals for 2-S are the same as reported in the S literature.

0 'H-NMR (CDCI 3 2.69 (dd, 1H), 2.83 1H), 3.26-3.30 (m 1H), 3.43 (brs, 2H), 3.83 (dd, 00 1H), 4.1 (dd, 1H), 6.59 (dd, 2H), 6.72 (dd, 2H).

The (R)-enantiomer of compound 2 was also prepared from compound 1-R.

'H-NMR (CDCI) 8 2.69 (dd, 1H), 2.83 1H), 3.26-3.30 (m IH), 3.43 (brs, 2H), 3.83 (dd, 1H), 4.1 (dd, 1H), 6.59 (dd, 2H), 6.72 (dd, 2H).

Preparation of (S)-Glycidyl N-Methylsulfonyl-p-Aminophenyl Ether Compound 2-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM and N,N-diisopropyl- N-ethylamine (0.45 ml, 2.6 mmol) were combined at 0°C. After stirring the latter mixture for minutes, methanesulfonyl chloride (0.2 ml, 2.6 mmol) was added dropwise at 0 C. After stirring over night, the reaction was extracted with water and washed with brine. The organic phase was dried over magnesium sulfate and evaporated. The non-volatile residue was purified with flash chromatography using ethyl acetate: DCM (30:70) solvent to give a white solid (m.p:106-108 0 C, 70% yield).

'H-NMR (CDCl 3 2.77 (dd, 1H), 2.92 1H), 2.95 3H), 3.34-3.36 (m 1H), 3.92 (dd, 1H), 4.24 (dd, 1H), 6.34 1H), 6.91 (dd, 2H), 7.19 (dd, 2H).

The (R)-enantiomer of compound 3 was also prepared starting with compound 2-R.

'H-NMR (CDCI 3 52.76 (dd, 1H), 2.92 1H), 2.95 3H), 3.34-3.36 (m IH), 3.92 (dd, 1H), 4.24 (dd, 1H), 6.36 1H), 6.91 (dd, 2H), 7.19 (dd, 2H).

WO 02/072542 PTUOI73 PCT/US02/07033 51 Preparation of 4 -Methanesulphonamidephenoxy)3.(NmethylI3,4-dichlorophenylethylamino)-2-propanol Compound 3-S (0.326g, 1.34 mmol) and N-methyl-3,4-dichloropenylethylamine (0.276g, 1.34 mmol) were dissolved in 5 ml ethanol and refluxed for 20 hours. The solvent was then evaporated and the residue purified by flash chromatography using dichioromethane: methanol (90: 10) solvent to give the product as a colorless oil (30% yield).

'H-NMR (CDCL 3 5 2.37 3H), 2.52-2.78 (in, 6H), 2.93 3H), 3.91, (dd, Ha, lH), 3.92 (s, 00 HP, 3.98-4.04 (in, I 6.86 (dd, 2H), 7.01 (dd, IlH), 7.17 (dd, 2H), 7.28 I1H), 7.33 (d, I H).

Compound 4-S was dissolved in ethanol and treated with HCl gas to provide the HCI salt as a white solid which complexes with 1 mol of water. Anal. Calcd for

C

19

H

24

N

2 0 4 SC1 2 .HCI.1H 2 0: C, 45.47; H 5.42; N, 5.58. Found: C, 43.87; H 5.41; N, 4.94.

The (R)-enantiomer of compound 4 was also prepared from compound 3-R.

'H-NMR (CDCI 3 )6 2.3 7 3H), 2.52-2.78 (in, 6H), 2.93 3H), 3.9 1, (dd, Ha, I 3.92 (s, HP, 3.98-4.04 (in, I 6.86 (dd, 2H), 7.01 (dd, I1H), 7.17 (dd, 2H), 7.28 IlH), 7.3 3 (d, I H).

Compound 4-R was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid which complexes with 1 mol of water. Anal. Calcd for

C

19

H

24

N

2 0 4 SC1 2 .HCI.1H 2 0: C, 45.47; H 5.42; N, 5.58. Found: C, 43.80; H 5.45; N, 5.27.

Preparation of 4 -Methanesulpbonamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol Compound 3-S (0.364g, 1.5 inmol) and 3, 4 -dichloropenylethylamine (0.284g, 0. 11 ml, rmol) were dissolved in 5 ml ethanol and refluxed for 5 hours. The solvent was evaporated and the non-volatile residue purified by flash chromatography using dichloromethane: methanol (90: 10) solvent to give the product as a colorless oil (80% yield).

'HI-NMR (CDCI 3 5 2.75-2.93 (in, 6H), 2.95 3.94, (dd, H-Ia, 1H), 3.96 HP, 1H), 4.00- 4.05 (in, I1H), 6.86 (dd, 7.04 (dd, I 7.17 (dd, 2H), 7.30 IlH), 7.35 I H).

WO 02/072542 PCT/US02/07033 O 52

O

Compound 5-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a Swhite solid. Anal. Calcd for C, 8

H

2 2

N

2 0 4 SCl 2 .HCI: C, 46.02; H 4.93; N, 5.96. Found: C, S 46.44; H 4.95; N, 5.78.

The (R)-enantiomer of compound 5 was also prepared from compound 4-R.

'H-NMR (CDCI 3 2.75-2.94 6H), 2.95 3H), 3.94, (dd, Ha, IH), 3.96 Hp, 1H), 3.99- 4.05 1 6.87 (dd, 2H), 7.04 (dd, 1 7.18 (dd, 2H), 7.30 1 7.35 1H).

00 0O Compound 5-R was dissolved in ethanol and treated with HCI gas to provide the HCI salt as S a white solid. Anal. Calcd for CH, 2 N,0 4

SCI

2 .HCl: C, 46.02; H 4.93; N, 5.96. Found: C, 46.29; H 5.06; N, 5.84.

The general reactions for the synthesis of representative compounds 6 and 8-15 are given in Scheme 2. The corresponding substituents are listed in Table 2.

SCHEME 2

CIH

H

H N O NHSO 2 CH, R-CHO NaB(AcO),H

H

1,2-Dichlorocthane CI HO CI NO

NHSOCH

3

R

6, 8-15 WO 02/072542 PCT/US02/07033 53 Table 2. Substitutents representing both S- and R-enantiomers Compound

R

6

CH

3 8

CH

s 9

C

3

H,

Phenyl 11 2-Fluorophenyl 12 3-Fluorophenyl 13 4-Fluorophenyl 14 2,6-Difluorophenyl 2,3,4-Trifluorophenyl General Method for preparation of compounds 6, 8-15.

Compound 5 (1 mmol) and the appropriate aldehyde (1 mmol) were dissolved in ml 1,2-dichloroethane and treated with sodium triacetoxyborohydride (1.4 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with saturated sodium bicarbonate. The water phase was extracted with 1,2-dichloroethane; the organic phase was dried over MgSO, and evaporated. The residue was purified with flash chromatography to give a colorless oil.

Preparation of 4 -Methanesulphonamidephenoxy)-3-(N-ethyl-3,4-dichlorophenylethylamino)-2-propanol 72% yield, solvent for flash chromatography DCM:MeOH (90:10). 'H-NMR (CDCI 3 1.03 3H), 2.58-2.80 8H), 2.91 3H), 3.88, (dd, Ha, 1H), 3.90 HP3, IH), 3.94- 3.96 1H), 6.83 (dd, 2H), 6.99 (dd, IH), 7.16 (dd, 2H), 7.25 1H), 7.31 1H).

Compound 6-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid which which complexes with 1 mol of water.

WO 02/072542 WO 92/72542PCTIUS02/07033 54 Preparation of (S)-1I eth an esulIphona mid ephen oxy)3-(N-pro pyl1-3,4-d ich lorophenylethylamino)-2-propanol IND 80% yield, solvent for flash chromatography DCM:MeOH (90: 10). 'H-NMR (CDCI 3 8 0.86 3H), 1.39-1.56 (in, 2H), 2.56-2.82 (in, 8H), 2.91 3H), 3.89, (dd, HaC, I 3.90 (s, HO3, I1H), 3.92-3.96 (in, IlH), 6.84 (dd, 2H), 6.99 (dd, I1H), 7.16 (dd, 2H), 7.25 I 7.31 I H).

Compound 8-S was dissolved in ethanol and treated with HCI gas to provide the HICI 00 salt as a white solid which which complexes with I inol of water.

Preparation of (S)-1-(4-Methanesulphonamidephenoxy)-3-(N-butyl-3,4-dichlorophenylethylamino)-2-propanol 74% yield, solvent for flash chromatography DCM:MeOH (90: 10). 'H-NMR (CDCI 3 8 0.88 1.22-1.30 (in, 2H), 1.36-1.45 (in, 2H), 2.44-2.80 (in, 8H), 2.89 3H), 3.88, (dd, Ha, I 3.89 F3, I 3.92-3.96 (mn, I 6.82 (dd, 2H), 6.98 (dd, I1H), 7.16 (dd, 2H), 7.24 IlH), 7.29 IRH).

Compound 9-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

Preparation of (S)-1-(4-Methanesulphonamidephenoxy)-3-(N-benzyl-3,4-dichloropbenylcthyianiino)-2-propanol yield, solvent for flash chroma-tography DCM:MeOH (90: 10). 'H-NMR (CDCI 3 2.62-2.84 (mn, 6H), 2.91 3 3.5 7 I1H), 3.79 I 3.84, HaC, IlH), 3.86 H P, I1H), 3.92-4.08 (mn, I 6.80 (dd, 2H), 6.92 (dd, I1H), 7.15 (dd, 2H), 7.19 I 7.24-7.36 (in, 6H).

Compound 10O-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid which which complexes with I mol of water.

Preparation of -(4-Methancsulphonamidephenoxy)-3-(N-(2-fluorobenzyl)-3,4dichlorophenylethylamino)-2-propanol (1 yield, solvent for flash chro-matography DCM:EtOAc (70:30). 'H-NMR (CDCI 3 2.69-2.88 (in, 6H), 2.93 3H), 3.68 IlH), 3.81 1H), 3.88, Ha, IR), 3.89 HO, WO 02/072542 PCTUS02O7033 I 4.01-4.06 (in, IlH), 6.83 (dd, 2H), 6.91 (dd, I 7.08 (dd, 2H), 7.14-7.20 (in, 3H), 7.22- 7.29 (in, 3H).

Compound I11-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid which which complexes with I mol of water.

Preparation of 4 -Mcthanesulphonamidephenoxy)-3-(N-(3.fluorobenzyl).3,4.

dichlorophenylethylamino)-2-propanol (1 2-S).

yield, solvent for flash chro-matography DCM:EtOAc (70:30). 'H-NMR (CDCI 3 00 8 2.69-2.88 (mn, 6H), 2.94 3H), 3.59 1H), 3.78 1H), 3.86, Ha, 1H), 3.88 HO3, I1H), 3.98-4.03 (in, I 6.83 (dd, 2H), 6.93 (dd, I 7.17 (dd, 2H), 7.16-7.21 (in, 3H), 7.24- 7.32 (mn, 3H).

Compound 1 2-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid which which complexes with 1 mol of water.

Preparation of 4 -Methanesulphonamidephenoxy)3(N.(4fluorobcnzl)-3,4dich lo rop henyiethyla min o)-2-p ropa nol (13-S).

yield, solvent for flash chro-matography DCM:EtOAc (70:30). 'H-NMR (CDCI 3 8 2.67-2.86 (mn, 6H), 2.94 3H), 3.55 1H), 3.76 1H), 3.85, Ha, IH), 3.87 HP, I 3.97-4.03 (in, I 6.82 (dd, 2H), 6.92 (dd, I 6.97 (dd, 2H), 7.14-7.20 (in, 5H), 7.29 IlH).

Compound 13-S was dissolved in ethanol and treated with HICI gas to provide the HCI salt as a white solid which which complexes with 1 mol of water.

Preparation of 1 4 -Mth anes u ph on amid ephnoxy)3.{(2,6dif] u orobenyl)-34dichlorophenylcthylamino)-2..propanoI (14-S).

yield, solvent system for flash chromatography DCM:EtOAc (70:30). 'H-NMR

(CDCI

3 8 2.67-2.81 (in, 6H), 2.94 3H), 3.77 1H), 3.85 lH), 3.89, Ha, 1H), 3.90 I 7.25 (dd, 2H).

Compound 14-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

WO 02/072542 WO 02/72542PCTUS02O7O33 56 N Preparation of 4 -Mcthanesulphonamidephenoxy).3-(N..(2,3,4.trifluorobenqyl) 3 4 -dichlorophenylethylamino)-2-propanoI (1 IND 65% yield, solvent for flash chromatography DCM:EtOAc (70:30). 'H-NMR (CDCl 3 8 2.65-2.80 (in, 6H), 2.95 3H), 3.68 1H), 3.78 1H), 3.87, Ha, IH), 3.89 HP, 1H), 4.00-4.04 (in, 1H), 6.83 (dd, l1H), 6.88-6.95 (in, 3H), 7.16 (dd, 2H), 7.18 (dd, 2H), 7.30 (dd, I H).

Compound 15-S was dissolved in ethanol and treated with HCl gas to provide the HCI salt as a white solid.

Preparation of 4 -Mcthanesulphonamidephenoxy)3(N-(2,3,4,5,6-pentafluoro.

benzyl)- 3 4 -dicblorophenylethylamino)-2-.propanoI (16-S).

yield, solvent for flash chromatography DCM:EtOAc (70:30). 'H-NMR (CDCI 3 8 2.58-2.79 (in, 6H), 2.93 3H), 3.41 (dd, I 3.61 (dd, I 4.08(d, 2H), 4.50-4.60 (in, I1H),6.87-6.93 (in, 3H), 7.00(d, IlH), 7-15(d, IH), 7.19 (dd, 2H-).

Compound 7 was prepared in two steps as shown in scheme 3.

WO 02/072542 WO 02/72542PCTUSO2O7033 00 57 SCHEME 3 HO NHSO 2 CHJ +HI2hr:n

CI

HO

Cl 'NaOMe 00 Ci

NHSO

2

CH

1 eO 0 7a

CI

HO

CI C HO2C H~ O NS 2 I1

OH

7 Preparation of 4 -Methancsulphonamidcphenoxy)-3-(N-(2-.butyroxyethyI)-3,4.

dichlorophenylethylamino)-2-propanol (7a-S).

With the general method, 0-Butyryl glycoaldehyde and compound 5 gave the (4-Methanesulphonamidephenoxy)3 -(N-(2-butyroxyethyl)-3 ,4-dichlorophenylethylamino)-2propanol in 85% yield as a colorless oil. This compound was purified with flash chromatography using DCM: Ethyl acetate (70:30) solvent.

WO 02/072542 WO 02/72542PCTUS02O 7033 58 'H-NMR (CDCI 3 $0.89 3H), 1.56-1.64 (in, 2H), 2.24 2H), 2.64-2.87 (in, 6H), 2.90 (s, 3H), 3.87-4.13 (in, 6H), 4.3 8-4.44 (in, I1H), 6.83 (dd, 2H), 6.99 (dd, I1H), 7.16 (dd, 2H), 7.25 IND (dd, I 7.31 1 H).

Preparation of (S)-l-(4-Methanesulphonamidephenoxy)-3-(N-(2-hydroxyethyl)-3,4dichlorophenylethylamino).2-propanol Reaction of compound 7a-S with sodium methoxide (2 equiv) gave compound 7-S in.

00 75% yield as a colorless oil. This compound was purified with flash chromatography using 0 DCM: MeOHI (90: 10) solvent.

'H-NMR (CDCl 3 6 2.72-2.86 (mn, 8H), 2.94 3H), 3.64, (dt, 21-1), 3.87 HP, IH), 3.89 (dd, Fla, I 3.98-4.04 (in, IlH), 6.84 (dd, 2H), 7.03 (dd, I1H), 7.17 (dd, 2H), 7.29 I H), 7.3 3 I H).

Compound 7-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

Synthesis of compound 16 is shown in Scheme 4.

WO 02/072542 WO 02/72542PCUIUS02/07033 59 SCHEME 4 0 2 N, Nr

H

GsF /DM

H

CH

3 SO-N N 7 "Ja H 1 6c CH 3 -SO 2

GI

/N-CH(CH 3 2 c 2 H 5 THF jH 2 C~n H2 1 6b

CI

CI NH2

;O

2

CH

3 WO 02/072542 PCT/US02/07033 0 CN Preparation of (S)-Glycidyl m-Nitrophenyl Ether (16a-S).

C 3-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF, and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was strried for 1 hour at room

C

I temperature, and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO 4 and evaporated.

The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl m-nitrophenyl ether (1.02 g 80% yield, m.p 44-5 0 C) as a yellowish solid.

'H-NMR (CDCI 3 8 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H), 4.38 (dd, 1H), 7.28 (dd, IH), 7.41(q, 1H), 7.67-7.87(m, 2H).

Preparation of (S)-Glycidyl m-Aminophenyl Ether (16b-S).

Compound 16a-S (0.5 g, 2.6 mmol) and %5 Pd/C(en) (10 of the weight of starting material) in 5 ml anhydrous THF was hydrogenated at ambient pressure and temperature for hours. The reaction mixture was filtered by using a membrane filter (13, 0.22 pm), and the filtrate was concentrated in vacuo. The resulting compound is a crude mixture of nitro group reduction and epoxide ring opening. Isolation of the desired compound was difficult because of the lability of the components of the mixture on silica gel. The product ratio of the

NO

2 reduction and ring opening (80:20) was determined on the basis of the integration ratio of the epoxide-ring protons from nitro group reduction and the methyl proton of the ring opened compound (98% total yield for the mixture).

'H-NMR (CDC 3 5 2.69 (dd, 1H), 2.83 (dt, 1H), 3.27-3.32 (m 1H), 3.43 (brs, 2H), 4.15 (dd, 1H), 4.27 (dd, 1H), 6.13-6.35 3H), 6.89-7.03 1H).

Preparation of (S)-Glycidyl N-Methylsulfonyl-m-Aminophenyl Ether (16c-S).

Compound 16b-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM, and N,Ndiisopropyl-N-ethylamine (0.45 ml, 2.6 mmol) was added at o0C. After stirring for minutes, methanesulfonyl chloride (0.2 ml, 2.6 mmol) was added to the reaction mixture at 0°C. After stirring overnight, the reaction mixture was extracted with water and washed with WO 02/072542 PCT/US02/07033 00 0 61

O

brine. The organic phase was dried and evaporated. The residue was purified with flash Schromatography using ethyl acetate:DCM (30:70) solvent to give a colorless oil (45% yield).

N 'H-NMR (CDC 3 5 2.75 (dd, 1H), 2.89 1H), 2.99 3H), 3.33-3.36 (m IH), 3.88 (dd, I 4.24 (dd, 1H), 6.70 (dd, 1H), 6.81 (dt, 1H), 7.16-7.23 2H), 7.52 1H).

S Preparation of (S)-l-(3-Methanesulphonamidephenoxy)3-(3,4-dichlorophenylethylamino)-2-propanol (16-S).

00 Compound 16c-S (0.364g, 1.5 mmol) and 3,4-dichloropenylethylamine (0.284g, 0.11 ml, 1.5 mmol) were dissolved in 5 ml ethanol and refluxed for 10 hours. Then, solvent was evaporated and the residue purified by flash chromatography using dichloromethane: methanol (90:10) solvent to give the product (55% yield).

'H-NMR (CDCI 3 8 2.75-2.95 6H), 3.01 3H), 3.96, (dd, Ha, 1H), 3.97 Hp, 1H), 3.99-4.05 1H), 6.71 (dd, 1H), 6.75 (dd, 1H), 6.82 1H), 7.05 (dd, 1H), 7.24 IH), 7.30 IH), 7.36 1H).

Compound 16-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

Compound 17-S was prepared as follows (Scheme WO 02/072542 WO 02/72542PCT/USO2/07033 00 6 IND

SCHEMES

NO 2 0NO 2 OH 2 N S'O0 CsFDMF g .0 H H 17a ci 00ethanol rellux CI 0 NH 2 CO

ON

I OH N ~c /Np-toluene-

C,

Oh sulfonic acidH 1 7c H 7 CP d/C H 2 H 2 "1 b C 0 N 1.C 3 -SO 2 C HO iN\/ 2. 2N HCI Cl N- Ph

H

1 7d 17 Preparation of (S)-Glycidyl o-Nitrophenyl Ether (17a-S) 2-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF. Cesium fluoride (3.02 g, 19.9 mmol) was added to the reaction. The reaction mixture was stirred for I hour at room temperature and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction was stirred for 16 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO 4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane WO 02/072542 PTUOI73 PCT/US02/07033 00 63 (50:50) solvent to give (S)-glycidyl o-nitrophenyl ether (1.21 g, 90% yield, m.p. 46-47'C) as a white solid.

INO H-M (CC 3 8 2.87 (dd, I1H), 2HNR(Dl.92 (t I 3.3 7-3.41 (m I1H), 4.14 (dd, IlH), 4.40 (dd, I 7.06 (dt, I 7.12 IlH), 7.5 3(dt, I 7.84 (dd, IlH).

Preparation of 2 -nitrophenoxy)-3-(3,4-dichlorophenylethylamino)2propanoI (17b-S).

00 Compound 17a-S (1.05 g, 5.4 mmol) and 3,4-dichloropenyl ethyl amine (1.02g, 0.8 ml, 5.4 mmol) were dissolved in 25 ml ethanol and refluxed for 12 hours. Then the solvent was evaporated and the residue recrystallized from ethylacetate-petroliun- ether to give the product (1.02 g, 99% yield, m.p. 73-74 0 C as a white solid.

'H-NMR (CDCI 3 8 2.75-2.94 (in, 6H), 4.02-4.18 (mn, 3H), 7.05 (dt, 3ff), 7.33 (dd, 2H), 7.53 (dt, I 7.8 7 (dd, I1H).

Preparation of 2 -phenyl-3-(N-phenylethylamino)-5-(4-nitrophenoxy methyl)oxazolidine(17c-S).

Compound 17b-S (1.02 g, 2.6 mmol), benzaldehyde (0.3 15 g, 0.3 ml, 2.96 inmol), and p-toluene suiphonic acid (catalytic amount) were dissolved in 50 ml of toluene and refluxed in a Dean Stark apparatus for 30 hours, cooled, and extracted with saturated sodium bicarbonate. The organic layer was dried over MgSO 4 and evaporated yielding a yellow oil as a mixture of stereoisoiners. The material was used directly for the next step.

'H-NMR (CDCl 3 862.61-2.99 (in, I OH), 3.56 (dd, IlH), 3.61 (dd, I 3.83 I1H), 4.03 IlH), 4.20 (dd, 2H), 4.32 (dd, 2H), 4.54-4.58 (in, I 4.64-4.69 (in, I1-H), 4.81 IlH), 4.94 I H), 6.88 (dd, I 6.93 (dd, I 7.04-7.21 (in, 6H), 7.26-7.43 (in, 12H), 7.51 IlH), 7.55 114), 7.8 5 (dd, I 7.8 8 (dd, I1H).

Preparation of 2 -phenyl-3-(N-phenylethylamino).5-(4-aminophcnoxy methyl)oxazo- Iidinc(17d-S).

Compound 17c-S (1.28 g, 2.7 minol) was dissolved in 30 ml ethanol. 2N sodium hydroxide(1.28 g) and PdIC 10) 128 g, 10 of the weight of starting material) was added to the solution. The reaction was hydrogenated at ambient pressure and temperature for 12 hours. The reaction mixture was filtered by using a membrane filter (13, 0.22 jim), and the WO 02/072542 PCT/US02/07033 0 64

O

C filtrate was concentrated in vacuo leaving a yellow oil. The latter was dissolved in DCM and Sextracted with water, dried over MgSO 4 and the solvent removed leaving a colorless oil (0.46 I g, 39% yield). The material was used directly in the next step.

SPreparation of l-(2-Methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethylamino)- 2-propanol (17-S).

OCompound 17d-S (0.460 g, 1.05 mmol) was dissolved in DCM and cooled to 0 0

C

00 followed by addition of diisopropylamine (0.149 g, 0.2 ml, 1.15 mmol) and O methanesulfonylchloride (0.132 g, 0.1 ml, 1.15 mmol). The reaction mixture was stirred at 0°C for 2 hours, then warmed to room temperature slowly, and stirred at room temperature for another 16 hours. Solvent was evaporated leaving a yellow brown oil. The latter was added to ml of IN HCI solution, stirred at room temperature for 4 hours and extracted with DCM.

The water layer was removed under reduced pressure, and the resulting solid was recrystallized from ethanol/ether to give the hydrochloride salt of compound 17-S.

'H-NMR (DMSO-d 6 8 2.34 3H), 2.93-3.39 6H), 3.94-4.10 2H), 4.15- 4.30 1H), 6.55-7.03 2H), 7.24- 7.60 5H), 8.74 1H).

The syntheses of compounds 18 and 19 are shown in scheme 6.

WO 02/072542 WO 02/72542PCT/US02/07033 00 SCHEME 6 c-IN.OH0 c-i CI NHSO 2

CH

3 L U N H 3 /N

NJ

(CH 3

CO)

2 0 /N N benzene 61: CI

NN

CI 0 C, C r ONS NHSCH 18 Preparation of l-( 4 -Metbanesulphonamidophenoxy)-3-(N-acetyl3,4-dichlorophenylethylamino)-2-propyl acetate (18-S).

Compound 5-S (0.303 g, 0.7 mmnol) and a catalytic amount of 4-(N,N-dimethylamino) pyridine. were dissolved in acetic anhydride (1 ml) and pyridine (I ml) and stirred at room temperature overnight. The reaction was poured into 10 ml ice-water and extracted with DCM..

The organic layer was dried over MgSO 4 and evaporated. The residue was purified with flash chromatography using ethyl acetate:DCM (30:70) solvent to give as a colorless oil (75% yield).

'H-NMR (CDCl 3 5 1.96 3H), 2.08 3H), 2.82 (dd, 3.39 (dd, 2H), 3.44 3H), 3.56 (dd, 2H), 4.07, (dd, 1-Ia, IHI), 4.11 (dd, HP, IH), 5.23-5.35 (in, 1H), 6.96 7.03 (dq, IH), 7.20 (dq, 2H), 7.3 0 (dd, IlH), 7.3 7 (dd, IlH).

Compound 18-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

WO 02/072542 WO 02/72542PCT/US02/07033 00 66 N Preparation of N-( 3 4 -dichlorophenyl)ethyl-5-(4-methanesulphonamidophenoxy) ct methyl-oxazolidine-2-one (19-S).

Compound 5-S (0.303 g, 0.7 mmol), 1, I'-carbonyldiimidazole 147 g, 0.906 mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine were dissolved in 10 ml benzene.

After 12 hours refluxing the solvent was evaporated, and the residue was purified with flash chromatography using ethyl acetate:DCM (30:70) solvent to give a colorless oil (85% yield).

'H-NMR (CDCI 3 8 2.88 2H), 2.95 3.42-3.62 (in, 4H), 4.02 (dd, 4.76-4.82 00 (in, I 6.51 I1H), 6.83 (dd, 2H), 7.09 (dd, IH), 7.20 (dd, 2H), 7.32 1H), 7.35 I H).

Compound 19-S was dissolved in ethanol and treated with HCI gas to provide the HICI salt as a white solid.

The synthesis of compound 20 is shown in Scheme 7.

SCHEME 7 N K 2 C0 3 0 +H 3 C-1

CH

3

SO

2 NHa acetone CH 3 SOi--N C NH 2 ethanol Cl

OH

ClN O N-SO2CH H I 2 WO 02/072542 PCT/US02/07033 00 O 67 Preparation of (S)-Glycidyl N-methyl-N-Methanesulfonyl-p-Aminophenyl Ether S S).

I A solution of compound 3-S (0.243 g, 1 mmol) and potassium carbonate (0.166 g, 1.2 mmol) in 20 ml acetone was stirred for I hour at room temperature, then methyl iodide (0.142 g, 0.062 ml, 1 mmol) was added dropwise at room temperature. After stirring for 8 hours, the reaction was filtered and the solvent evaporated to furnish a white solid that was used directly in the next step (0.2 g, 78% yield).

oO 'H-NMR (CDC 3 1) 8 2.76 (dd, 1H), 2.83 3H), 2.92 1H), 3.28 3H), 3.33-3.39 (m 1H), S3.93 (dd, 1H), 4.24 (dd, 1H), 6.92 (dd, 2H), 7.29 (dd, 2H).

Preparation of (S)-l-(4-N-methyl-methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol Compound 20a-S (0.2 g, 0.8 mmol) and 3,4-dichloropenylethylamine (0.147g, 0.11 ml, 0.8 mmol) were dissolved in 5 ml ethanol, refluxed for 5 hours, and relieved of solvent by evaporation. The residue was purified by flash chromatography using dichloromethane:methanol (90:10) solvent to give the product as a white solid (80% yield).

'H-NMR (CDCl 3 8 2.72-2.78 2H), 2.80 3H), 2.83-2.93 4H), 3.24 3H), 3.93, (d, 2H), 4.00-4.04 1H), 6.85 (dd, 2H), 7.02 (dd, 1H), 7.24 (dd, 2H), 7.26 1H), 7.31 (d, 1H).

Compound 20-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

Compound 21 was prepared in a manner similar to compound 5 (Scheme 8) WO 02/072542 WO 02/72542PCT/US02/07033 68 SCHEME 8 IH +s c l/ \H H 2 N S-N 21a 001 ethanol

CIC

OH 0 CI N' 0N~-S

H

0 21 Preparation of (S)-Glycidyl N-benzenesulfonyl-p-Aminophenyl Ether (21 a-S).

Compound 2-S (0.423 g, 2.56 mmol) in 20 ml anhydrous DCM at 0 0 C was combined with N,N-diisopropyl-N-ethylamine (0.364 g, 0.49 ml, 2.82 mmol). After stirring for minutes, benzenesulfonyl chloride (0.497 g, 0.36 ml, 2.82 mmol) was added dropwise at 0 0

C,

and the reaction was stirred for 3 hours. The reaction solution was extracted with water and washed with brine; the organic phase dried and evaporated. The residue was purified with flash chromatography using ethyl acetate:DCM (30:70) solvent to give a white solid yield).

'H-NMVR (CDCI 3 562.74 (dd, 1H), 2.90 11-1), 3.3 1-3.36 (m 1HI), 3.86 (dd, I 4.18 (dd, 1 6.66 1 6.77 (dd, 2H), 6.97 (dd, 211), 7.42 7.52 (dd, I 7.70 (dd, 2H).

WO 02/072542 PCT/US02/07033 0 69 Compound 21a-S (0.620g, 2.0 mmol) and 3,4-dichloropenylethylamine (0.386g, 0.30 ml, 2.0 mmol) were dissolved in 25 ml ethanol and refluxed for 16 hours. The solvent was then evaporated and the residue was purified by flash chromatography using C dichloromethane: methanol (90:10) solvent to give the product (90% yield).

'H-NMR (CDCI 3 2.73-2.94 6H), 3.89, (dd, Ha, 1H), 3.91 Hp, 1H), 3.97-4.01 (m, 1 6.74 (dd, 2H), 6.94 (dd, 2H), 7.03 (dd, I 7.29 1H), 7.34 1 7.43 2H), 7.52 (dd, 1H), 7.67 (dd, 2H).

Compound 21-S was dissolved in ethanol and treated with HCI gas to provide the HCI salt as a white solid.

The synthesis of compound 22 was accomplished in a single step (Scheme 9).

SCHEME 9

C

1 C 0 ^NH

OH

HI CI N a NO2 0 2 N H N 22 Preparation of 4 -Nitrophenoxy)3-(3,4-dichlorophenylethylamino)2propanol (22-

S)

Compound 1-S (0.195g, I mmol) and 3,4-dichloropenylethylamine (0.190g, 0.15 ml, 1 mmol) were dissolved in 5 ml ethanol and refluxed for 2 hours. After 2 hours, a solid precipitated from the reaction (0.296 g, 77% yield). It proved to be pure by NMR and TLC.

'H-NMR (CDCl 3 8 2.74-2.80 3H), 2.86-2.97 3H), 4.02-4.08 3H), 6.96 (dd, 2H), 7.04 (dd, 1H), 7.31 1H), 7.36 1H), 8.20 (dd, 2H).

69A Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not C, intended to exclude other additives, components, integers or steps.

A reference herein to a patent document or other matter which is given as prior 00 art is not to be taken as an admission that that document or matter was known or that Sthe information it contains was part of the common general knowledge as at the priority date of any of the claims.

This application is a divisional of Australian Patent Application No: 2002250256. The entire disclosures of both Australian Patent Application No: 2002250256 and its corresponding International Patent Application No: PCT/US02/07033 are incorporated herein by way of reference.

Claims (19)

1. A compound selected from the group consisting of or (S)-enantiomers and racemic mixtures of compounds of the formula: R 9 Rio A-B- 18 R 1

2 R11 wherein one of R 9 Rio, R, 2 and is 0 "R13 R17 where R, 3 is alkyl, aralkyl or aryl; where R 7 is H or lower alkyl; and the others of R, RIo, R, 2 and are H, F, Cl, I or R wherein R is lower alkyl; or: A-B- wherein R 9 Ro, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I, and R wherein R is lower alkyl, and R, 3 is alkyl aralkyl or aryl; WO 02/072542 PCT/US02/07033 00 71 O wherein A is selected from the group consisting of: R 3 R 00 0 R1 wherein R, and R, are independently H or F; R 2 R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, or R 2 and R 3 taken together are O-CH 2 -O; R4 R3 R R2 Ri wherein R 4 and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, R 3 is independently O, S, NH or NR, R 2 R 3 R26 R2 /yg WO 02/072542 PCT/US02/07033 72 O C 1 wherein R 4 and R, are independently selected from the group consisting of SH, F, Cl, Br, I and OR where R is lower alkyl, R 2 is independently O, S, NH or NR, R 3 Sis N; and R 16 is C-alkyl, C-aralkyl or C-aryl; R3 S R 4 R 00 Ri wherein R, through R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, or R 2 and R 3 taken together are O-CH 2 -O; R3 /R wherein R 2 and R 3 are independently selected from the group consisting of 0, S, NH or NR where R is lower alkyl, or R 2 and R 3 taken ogether are O-CH 2 and R 4 is N; R R In wherein R 2 and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; and R 4 is N; WO 02/072542 PCT/US02/07033 00 0 73 C N wherein R, is selected from the group consisting of O, S, NH and NR where R is Slower alkyl; R 2 is N, and R 3 and R 4 are independently selected from the group Sconsisting of H, F, CI, Br, I and OR where R is lower alkyl; R3 4 SR 2 R 00 1 wherein R, is selected from the group consisting of O, S, NH and NR where R is lower alkyl; R, and R 4 are N, and R 3 is independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; RR R R4 wherein R, is selected from the group consisting of O, S, NH and NR where R is lower alkyl; R 2 is selected from the group consisting of H, F, CI, Br, I and OR where R is lower alkyl; and R 3 and R 4 are N; x R4 Ri lower alky; and R2, R3 and R4 are N; Rr WO 02/072542 PCT/US02/07033 00 O 74 O wherein R, and R 3 are independently selected from the group consisting of O, S, NH Sand NR where R is lower alkyl; and R 2 R 2 and R 4 are independently selected from the Sgroup consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R3 mn R2 N R4 R R1 wherein R, and R, are independently selected from the group consisting of O, S, NH and NR where R is lower alkyl; and R 2 and R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; Ri XR2 XI xl X1 wherein Xl is C-R 3 or N, X 2 is C-R 4 or N, X 3 is C-R 4 or N where R-R 4 are independently selected from the group consisting of O, S, NH and NR where R is lower alkyl, or where R, and R 2 taken together are O-CH 2 -O; and wherein B is selected from the group consisting of: WO 02/072542 PCT/US02/07033 00 O CI wherein R 6 and R 6 are independently H or F; and R, is H, lower n-alkyl, CH 2 Ar, t CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CHF 2 Ar; and R 8 is OH, OR, where R is lower alkyl, or F; Ci H H RR 00 O wherein R 6 and are independently H or F; R 7 is CH 2 and Rg is O; R8 wherein R and R, are independently CH 2 CHR or CR 2 where R is lower alkyl; and R 8 is OH, OR, where R is lower alkyl, or F; H H (CH R wherein RP and R, are independently C-I 2 CHR or CR 2 where R is lower alkyl; and R, is OH, OR, where R is lower alkyl, or F; (CH2)n H H Re R7 R8 wherein R and R, are independently CI 2 CHR or CR, where R is lower alkyl; Rs is OH, OR, where R is lower alkyl, or F; and n=l-3; and WO 02/072542 PCT/US02/07033 00 0 76 O C pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and t mixtures of the foregoing. 1 2. The compound of claim 1 in combination with a suitable pharmaceutical carrier.

3. The compound of claim 1 selected from and enantiomers and mixtures Sthereof of compounds selected from the group consisting of: 00 R H R 9 R3 R 1 Re R& R 7 R 8 H R12 R11 wherein R, and R 5 are independently H or F; and when R, and R, are H, R 2 R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and R 2 and R 3 taken together are O-CI-1 2 R 6 and are independently H or F; R, is selected from the group consisting of lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2 3 4 ,5, 6 -pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; RI 0 and R, 2 are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; and R 1 3 is alkyl, aralkyl or aryl; and when one of R, or R, is F and the other is H or F, R 2 R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl and R 2 and R 3 taken together are O-CH 2 R 6 and are independently H or F; R, is selected from the group consisting of H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,

4- WO 02/072542 PCT/US02/07033 77 fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R 8 is OH or F; R 9 R 0 i, and R, 2 are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; and R, 3 is alkyl, aralkyl or aryl; wherein R, and R, are independently H or F; R 2 is N; R 3 is O, S, NH or NR where R is lower alkyl; R 4 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, R 6 and R 6 are independently H or F; R 7 is selected from the group consisting of H, lower n-alkyl,CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; Rio, and R, 2 are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; R,3 is alkyl, aralkyl or aryl; and R, 6 is C-alkyl, C-aralkyl or C-aryl; wherein R, and R, are independently H or F; R 2 is independently O, S, NH or NR where R is lower alkyl; R 3 is N; R 4 is selected from the group consisting of H, F, Cl, WO 02/072542 PCT/US02/07033 78 Br, I and OR wherein R is lower alkyl, R 6 and R 6 are independently H or F; R 7 is selected from the group consisting of H, lower n-alkyl,CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr and CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 R, 0 and R,, are independently selected from the group consisting of H, F, Cl, Br I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; and R, 6 is C-alkyl, C-aralkyl, or C-aryl; S4 wherein R, through R, are independently selected from the group consisting of H, F, Cl, Br, I and OR,4, and R 2 AND R 3 taken together are O-CH 2 R 6 and R' are independently H or F; R 7 is CH 2 R 8 is 0; RIo, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R,3 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl; and is lower alkyl; wherein R, and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 2 is O, S, NH or R 3 is N; R and R,' are independently H or F; R, is C-I12; R, is O; Ro, and R, 2 are independently WO 02/072542 PCT/US02/07033 79 selected from the group consisting of H, F, CI, Br, I and lower alkyl; R13 is alkyl, aralkyl or aryl; is lower alkyl; and R, 6 is C-alkyl, C-aralkyl or C-aryl; R12 R 11 wherein R, and R, are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 2 is N; R 3 is O, S, NH or NR15; R6 and R6' are independently H or F; R7 is CH2, R8 is O, R9, RIO, R11 and R12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R13 is alkyl, aralkyl or aryl; R15 is lower alkyl; and R16 is C-alkyl, C-aralkyl or C- aryl; wherein R, and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR14; R 2 and R 3 are independently selected from the group consisting ofF, Cl, Br, I, and and R 2 and R 3 taken together are O-CH2-O; R, and R, are independently CH 2 CHR,, or C(R, 5 2 R, is OH, OR, where R is lower alkyl, or F; R9, RIo, R, and R 12 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R,3 is alkyl, aralkyl or aryl; and Rt, is C-alkyl, C-aralkyl or C-aryl; WO 02/072542 PTUOI73 PCT/US02/07033 R R R9Rio N -R 13 R 1 6 N N/ 00 wherein R, and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR R 2 is selected from the group consisting of 0, S, NH or R 3 is N; R

5 R 6 and are independently CH 2 CHR, 5 or C(R, 5 2 R 8 is OH, OR, where R is lower alkyl, or F; R 9 Rio, R, I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R1 3 is alkyl, aralkyl or aryl; is C-alkyl, C-aralkyl or C-aryl; RI, is lower alkyl; and R, 6 is C-alkyl, C-aralkyl, or C-aryl; R R k R 6R R io R 1 RlR6 N\ (wherein R, and R 4 are independently selected from the group consisting of H, F, Cl, Br, Iand OR 4 R 2 is N; R 3 is selected from the group consisting of 0, S, NH and NR R 5 R 6 and R 7 are independently CH 2 CHR, 5 or C(R 1 5 2 R, is OH, OR, where R is lower alkyl, or F; R9, RIO, R, I and R, 2 are independently selected from the group consisting of H, F, C1, Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl, is lower alkyl; and R, 6 is C-alkyl, C-aralkyl, or C-aryl; WO 02/072542 WO 02/72542PCT/US02/07033 00 81 R R5 IN R9 RioR 00 wherein RI, R 2 R 3 RA and R, are independently selected from the group consisting of H, F, Cl, Br, I and ORW and hr R2and R 3 taken together are O-CH1 2 R 6 and R 7 are independently CH 2 ,CHR, 5 or C(R, 5 2 R, is OH, OR, where R. is lower alkyl, or F; R 9 Rio, RII and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl, and is lower alkyl; and n=1-3; R 5R 9 R 1 0 (CH\H ar idpedntyCHCH R 5 r, CR) 2 8 iOHO R1er R11oe lkl rF wren R, Rand R are independently selected fr the group consisting of H, F,Cl Br, I and lower alkyl, R 13 is alkyl, aralkyl or aryl; is lower alkyl; R, 6 is C-alkyl, C- aralkyl or C-aryl; and n= 1-3; WO 02/072542 WO 02/72542PCT/US02/07033 00 82 /3 Pe5R o ciRI H H '0 R13 R1 Fa H Pbr 12 R11' 00 wherein R 4 and R, are independently selected form the group consisting of H, F, CI, Br, I and OR where R is lower alkyl; R 2 is N; R 3 is 0, S, NH or R 6 and R, are independently CH 2 CHR, 5 or C(R 15 2 R, is OH, OR, where R is lower alkyl, or F; R 9 1 R 10 I and R 1 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; RI, is lower alkyl; R, 6 is C-alkyl, C- aralkyl or C-aryl; and n=1 -3; R R5 CH 2 R5 R 9 z A wherein R, R 2 R 3 R 4 and R, are independently selected from the group g of H, F, Cl, Br, I and OR where R is lower alkyl, and where R 2 and R 3 taken together are O-CH 2 0; R 6 and R 7 are independently CH 2 CHR, 5 or C(R, 5 2 R 8 is OH, OR, where R is lower alkyl, or F; R 9 Rio, R, and R 12 are independently selected from the group consisting of H, F, CI, Br, I or lower alkyl, RD 3 is alkyl, aralkyl or aryl; is lower alkyl; and n=1-3; WO 02/072542 WO 02/72542PCT/U SO2/0 7033 00 83 R R R 91 0 C IN 16(C5 H 00 wherein R 4 and R5 are independently selected form the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 2 iS 0, S, NH or NR 1 5 R 3 is N; R. and R, are independently CH 2 CHR, 5 or C(R, 5 2 R 8 is OH, OR, where R is lower alkyl, or F; Rq, RIO, R, Iand R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R 1 3 is alkyl, aralkyl or aryl; R, 5 is lower alkyl; R, 6 is C-alkyl, C- aralkyl or C-aryl; R, 6 is C-alkyl, C-aralkyl or C-aryl; and n=1-3; R 5R 9 10 Q H\ ,R 13 R 1 R 6 ,,K 7 R 8 H (CH 2 )n R 12 R1 wherein R 4 and R, are independently selected form the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is N; R 3 is 0, S, NH or NR, 5; R 6 and R 7 are independently CH 2 CHR, or C(R, 5 2 R, is OH, OR, where R is lower alkyl, or F; R 9 RIO) RI, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl, R, 3 is alkyl, aralkyl or aryl; is lower alkyl; R, 6 is C-alkyl, C- aralkyl or C-aryl, and n=1 -3; WO 02/072542 PCT/US02/07033 00 84 O R3 R R4 Rs R13 IN R R5R 5 13 Ri N R. Re R7 R8 R12 R11 00 wherein R, is selected from the group consisting of O, S, NH and R 2 R3 and R 4 O are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is H; R 6 and R' are independently H or F; R, is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; RO, and R,, are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R,3 is alkyl, aralkyl or aryl; and R,5 is lower alkyl; R3 R R4, R7 7 R9 Rio R13 R 1 R6 RS H O H R 1 2 Ril wherein R, is selected from the group consisting of O, S, NH and R 2 and R3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and R, and R 3 taken together are O-CH2-O; R4, R, and R are independently CH 2 CHR,, or C(R, 5 2 R, is H, R, is OH, OR, where R is lower alkyl, or F; R9, Rio, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; is alkyl, aralkyl or aryl; and is lower alkyl; WO 02/072542 WO 02/72542PCT/US02/07033 00 4 3 R 9 Rio N, R 6

6 \Ix H 00 wherein R, 1 is selected from the group consisting of 0, S, NH and NR, 15 P. 2 and P. 3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and R 2 and R 3 taken together are O-CH 2 P. 4 isN; R 5 is H; R 6 and R,6 are independently H or F; RJS is4, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6- difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 RIO, P. 11 and P. 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and R,, is lower alkyl; Rz- R 55RR\5 -R 13 R 8 I\ H wherein R, 1 and R 2 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R. 3 is selected from the group consisting of 0, S, NH and NR 1 5 R 4 is N; R, is H; R. and P.g are independently H or F; R. 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3 ,4-trifluorophenyl, or 2 ,3,4,5,6-pentafluorophenyl; is OH, OR, where R is lower alkyl, or F; R. 9 Rio, RI I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; P. 13 is alkyl, aralkyl or aryl; and P., 5 is lower alkyl; WO 02/072542 PCT/US02/07033 00 0 86 O R3 R9 Rio q SR2 R5 R5 R9 R R13 IT R 6 R6' R 7 R 8 H 0 R 12 R 11 00 wherein R, is selected from the group consisting of O, S, NH and NR,s; R2 is N; R 3 0 and R 4 are is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is H, R 6 and are independently H or F; R7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 Ro, and R,2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R,3 is alkyl, aralkyl or aryl; and is lower alkyl; R 3 R R 7 R 7 R9 Rio R 5 R13 Ri R6 R8 H R 8 H R12 R11 wherein R, is selected from the group consisting of O, S, NH and R 2 is N; R 3 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R 4 R, and R6 are independently CH,, CHRi or 2 R7 is H; R, is OH, OR, where R is lower alkyl, or F; R 9 Ri 0 and are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R,3 is alkyl, aralkyl or aryl; and is lower alkyl; WOD 02/072542 PCT/US02/07033 00 87 Ct R3 IDR 2 R 5 R 5 R13 Ri Ar R 6 R 6 R 7 R 8 \/H _R 12 R 11 00 wherein R, is selected from the group consisting of 0, 8, NH and NR 1 5 R 3 is selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkly; R 2 and R4 are N; R, is H; R. and R 6 are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3 ,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R. is OH, OR, where R is lower alkyl, or F; R9, RIO, R, I and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; RD 3 is alkyl, aralkyl or aryl; and is lower alkyl; R R 5 R 5 1R 3 Ri N R 6 R 6 K R 8 H wherein R, is selected from the group consisting of 0, S, NH and R 2 is selected from the group consisting of H, F, Cl, Br, I and Or where R is lower alkyl; R 3 and R 4 are N; R5 is H; R 6 and R 6 are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH2Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R 8 is OH, OR, where R is lower alkyl, or F; R 9 RIO, RI 1 and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R13 is alkyl, aralkyl or aryl; and is lower alkyl; WO 02/072542 WO 02/72542PCTIJS02O7033 00 88 R/ RRR1 ciR 6 R 6 I 7 H 00 wherein R, is selected from a group consisting of 0, S, NH or NR1 5; R 2 R 3 and R 4 C) are N; R, isH,R 6 and R 6 are independently H or F; R7 is selected from the group consisting of H, lower alkyl, CH 2 Ar, CH 2 CI- 2 Ar, CH 2 CH FAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; Rg is OH, OR, where R is lower alkyl, or F; R 9 Rio, RI, and are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R 13 is alkyl, aralkyl or aryl; and is lower alkyl; R2\ R3 Re R 6 R 7 R 8 /H wherein R, and R 3 are independently selected from the group consisting of 0, S, NH and R 2 R 2 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is H; R. and R 6 are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 C HFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R9, R, 0 and are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; RD 3 is alkyl, aralkyl or aryl; and is lower alkyl; WO 02/072542 PCT/US02/07033 00 89 O R3 R2 R R9 .Rio Rs Rs 5 13 Ri N O Rr R6- R7 R8 H 00 00 R12 R11 wherein R, and R, are independently selected from the group consisting of O, S, NH and NR,5; R2', R 3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R, is H; RP and RP' are independently H or F; R 7 is H, lower alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, or 2 ,3,4,5,6-pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; Ro, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; and R, 5 is lower alkyl; R3 R 4 I/4%R k R 9 R io 0 R2 |R 6 RR R13 R2 1- N 0 R1 R7 R 8 R12 R11 wherein R, and R4 are independently selected from the group consisting of O, S, NH and R, and R 3 are independently selected from the group consisting of H, F, Cl, Br, I and OR where RI 4 and R 2 and R 3 taken together are O-CH 2 R, and R, are independently CH 2 CHR,, or C(R, 5 2 R 8 is OH, OR, where R is lower alkyl, or F; R 9 WO 02/072542 WO 02/72542PCI/UiS02/07033 Rjo 0 and R 12 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R, 3 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl and R,, is lower alkyl; R8 H wherein R, and R 2 are independently selected from the group consisting of 0, S, NH and R 2 R 3 and (4 are independently selected from the group consisting of H, F, Cl, Br, I and ORW 4 and (3 and R(4 taken together are O-CH 2 5, R 6 and (7 are *independently CH 2 CHR, 5 or C(R, 5 2 R, is OH or F; R9, Rio, RI I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I ander alkyl; R, 3 is alkyl, aralkyl or aryl; R,4 is C-alkyl, C-aralkyl or C-aryl, and R, 5 is lower alkyl; X3_ RR 1 R R 6 R 6 R 7 R8H wherein R, R 2 R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and OR where R is lower alkyl; and where R, and R 2 taken together are 0- WO 02/072542 WO 02/72542PCT/US02/07033 00 91 ;CH4 2 R, is H, R 6 and R 6 are independently H or F; R 7 isHo oe yC 2 Ar CH 2 CH 2 Ar, CH 2 CHFAr or CH 2 CF 2 Ar, where Ar is aryl, 2-fluorophenyl, 3- IND fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,4,5,6- pentafluorophenyl; R, is OH, OR, where R is lower alkyl, or F; R 9 Rio, R, and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I and lower alkyl; R1 3 is alkyl, aralkyl or aryl; RI15 is lower alkyl; and XI is C-R3 or N; X2 is C- R4 or N; and X3 is C-R4' or N; 00 RR 6 R 8 H wherein R 2 R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I and ORW 4 and where R, and R 2 taken together are O-CH 2 R 5 R6 and R 7 are independently CH 2 CHR, 5 or C(R 15 2 R, is OH, OR, where R is lower alkyl, or F; R(9, Rio, R, I and R, 2 are independently selected from the group consisting of H, F, Cl, Br, I or lower alkyl; R 13 is alkyl, aralkyl or aryl; R, 4 is C-alkyl, C-aralkyl or C-aryl; R,, is lower alkyl; and X, is C-R 2 or N; X 2 is C-R 3 or N; and X 3 is C-R 4 or N. 4. A compound of claim 1 selected from the group consisting of the or forms of: I -(4-methanesulphonamidepheoxy)3 -(N-methyl-3 ,4-dichlorophenylethylamino)-2- propanol; 1 -(4-Methanesulphonamidephenoxy)-3 ,4-dichlorophenylethyl-amino)- 2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 -(N-ethyl-3 ,4-dichloro-phenylethylamino)-2- propanol; 1 4 -Methanesulphonamidephenoxy)3 -(N-propyl-3 ,4-d ichioro-phenylethylami no)-2- WO 02/072542 WO 02/72542PCTUS02IO7O33 00 92 N propanol; I -(4-Methanesulphonamidephenoxy)-3 -(N-butyl-3 ,4-dichloro-phenylethylamino)-2- IND propanol; I -(4-Methanesuiphonam idephenoxy)-3 -(N-benzyl-3 ,4-dichloro-phenylethylamino)-2- propanol; 1 -(4-Methanesulphonamidephenoxy)-3 -(N-(2-fluorobenzyl)-3 ,4-dichlorophenylethyl- amino)-2-propanol; 00 1 -(4-Methanesulphonamidephenoxy)-3 -fluorobenzyl)-3 ,4-dichlorophenylethyl- amino)-2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 -fluorobenzyl)-3 ,4-dichloro- phenylethylamino)-2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 fluorobenzyl)-3 ,4-dichlorophenyl- ethylamino)-2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 ,4-tri fluorobenzyl)-3 ,4-dichloro- phenylethylamino)-2-propanol; I -(4-Methanesulphonamidephenoxy)-3 ,3 ,4,5,6-pentafluoro-benzyl)-3 ,4-di- chlorophenylethylamino)-2-propanol; 1 -(4-Methanesulphonamidephenoxy)-3 -(N-(2-hydroxyethyl)-3,4-dichlorophenylethyl- amino)-2-propanol; 1 -Methanesulphonamidephenoxy)3 ,4-dichlorophenylethyl-amino)-2-propanol; I -(2-Methanesulphonamidephenoxy)-3 ,4-dichlorophenyl-ethylamino)-2-propanol; I -(4-Methanesulphonamidophenoxy)-3-(N-acetyl-3 ,4-dichloro-phenylethylamino)-2- propyl acetate; N-(3 4 -dichlorophenyl)ethyl-5-(4-methanesulphonamidophenoxy)methyl-oxazolidine. 2-one; I -(4-N-methyl-methanesulphonamidephenoxy)-3 ,4-dichloro-phenylethylamino)-2- propanol; I 4 -benzenesulphonamidophenoxy)-3-(3,4- di chloro..phenyl ethyl -amino-2- propanol; I 4 -Nitrophenoxy)3-(3,4-dichlorophenylethylamino)-2propanol; mixtures thereof and pharmaceutically acceptable salts thereof. WO 02/072542 PCT/US02/07033 00 93 A method of treating neurodegeneration associated with a pathological condition Scharacterized by lowered brain-tissue pH, said method comprising administering to a N patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brian-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of the compounds of claim 1. 00 6. A method of treating neurodegeneration associated with a pathological condition O characterized by lowered brain-tissue pH, said method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brain-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of: zolantidine dimaleate; 2 4 -chloroanilino)-4-(4-phenylpiperazino)cyclopent-2-en- 1-one; haloperidol; cirazoline; 1,10-phenanthroline; 6-[2-(4-imidazolyl)ethylamino]- N-(4-trifluoromethylphenyl)heptanecarboxamide; methanesulfonamidophenoxy)-3-(N-methyl-3,4-dichlorophenylethylamine)-2- propanol hydrochloride (AM92016, compound 93); 3-[[4-(4-chlorophenyl)piperazin- 1-yl]methyl]-l H-pyrrolo[2,3-b]pyridine; 8-[2-(1,4-benzodiaxan-2- ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione; (±)-8-hydroxy-2- dipropylaminotetralin hydrobromide; (+)-7-hydroxy-2-dipropylaminotetralin hydrobromide; 8-[3-(4-fluorophenoxy)propyl]-l-phenyl-1,3,8-triazospiro[4.5]-decan- 4-one (AMI 193); PPHT; 4 4 -fluorobenzoyl)-1-(4-phenylbutyl)piperidine; 2-(2- benzofuranyl)-2-imidazoline hydrochloride (2-BFI); benextramine; trifluoperidol; clobenpropit; and benoxathian.

7. A method of treating neurodegeneration associated with a pathological condition characterized by lowered brain-tissue pH, said method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound having enhanced NMDA receptor blocking activity at said lowered brain-tissue pH over normal brain-tissue pH, said compound being selected from the group consisting of(R)- or (S)-enantiomers or racemix mixtures thereof of a compound of the formula: WO 02/072542 WO 02/72542PCTIUS02/07033 A-B- wherein one of R 9 Rio, R 1 0, R, 2 and R 18 is 0 where R 13 is alkyl, aralkyl or aryl; where RP. is H or lower alkyl; and the others of R9, RIO, RI 1 R, 2 and are H, F, Cl, I or R wherein R is lower alkyl; or: A-B- wherein R 9 RIO, RI 1 and R, 2 are independently selected from the group consisting of H, F, Cl, Br, 1, and R whcrein R is lower alkyl, and R 13 is alkyl aralkyl or aryl; WO 02/072542 PCT/US02/07033 00 8 Swherein A is a bulky, ring-containing group; D and wherein B is selected from the group consisting of: H H R 6 7 R 8 00 0 wherein R 6 and are independently H or F; and R, is H, lower n-alkyl, CH 2 Ar, CH 2 CH 2 Ar, CH 2 CHFAr, or CH 2 CHF 2 Ar; and R, is OH, OR, where R is lower alkyl, or F; H H RS' R R8 wherein R. and R' are independently H or F; R 7 is CH 2 and R, is O; RR R 6 7 R8 wherein R 6 and R, are independently CH,, CHR or CR 2 where R is lower alkyl; and R, is OH or F; H H R(C R7 R8 (CH n WO 02/072542 PCT/USO2/07033 00 96 wherein R 6 and R, are independently CH 2 CHR or CR 2 where R is lower alkyl; and R, is OH, OR, where R is lower alkyl, or F; IND(C H 2)n H H FRe R7 R8 00 O wherein R, and R, are independently CH 2 CHR or CR, where R is lower alkyl; R, is OH or F; and n=1-3; and pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures, and mixtures of the foregoing.

8. A method for treating a pathological condition characterized by lowered brain-tissue pH, said condition being selected from the group consisting of hypoxia resulting from stroke, traumatic brain injury, global ischemia resulting from cardiac surgery, hypoxia resulting from cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, status epilepticus, neuropathic pain, inflammatory pain, chronic pain, vascular dementia and glioma tumors, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound selected from the group consisting of the compounds of claim 8 and the following compounds: zolantidine dimaleate; 2-(4-chloroanilino)- 4 4 -phenylpiperazino)cyclopent-2-en- I1-one; haloperidol; cirazoline; 1,10-phenanthroline; 6-[2-(4-imidazolyl)ethylamino]-N-(4- trifluoromethylphenyl)heptanecarboxamide; I -(4-methancsulfonamidophenoxy)- 3-(N-methyl-3, 4 -dichlorophenylethylamine)-2-propanol hydrochloride (AM92016, compound 93); 3-[[4-(4-chlorophenyl)piperazin- I -yl]methyl]- 1 H-pyrrolo[2,3- b]pyridine; 4 -benzodiaxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9- dione; 8 -hydroxy-2-dipropylaminotetralin hydrobromide; (+)-7-hydroxy-2- dipropylaminotetralin hydrobromide; 8 3 -(4-fluorophenoxy)propyl]- 1-phenyl-1,3,8- triazospiro[4.5]-decan-4-one (AMI 193); PPHT; 4-(4-fluorobenzoyl)- 1-(4- WO 02/072542 PCTIUS02/07033 00 0 97 0 phenylbutyl)piperidine; 2 -(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI); benextramine; trifluoperidol; clobenpropit; and benoxathian.

9. The method of claim 9 wherein said pathological condition is status epilepticus.

10. A method of making the or form of a compound having the formula: 00 O-R2 R3 Cl N O RI H wherein R, is CH, or H, R 2 is H, and R 3 is selected from the group consisting of NHSO 2 CH3, N(CH 3 )SO 2 CH 3 NHSO 2 Ph and NO 2 said method comprising reacting an or (R)-glycidyl (R)-R 3 -phenyl ether with N-methyl-3,4- dichlorophenylethylamine.to form the compound wherein R, is CH 3 or with 3,4- dichlorophenylethylamine to form the compound wherein R, is H.

11. The method of claim 10 further comprising forming a further compound of said formula wherein R, is selected from the group consisting of C 2 C3H,, C 4 H,, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluorobenzyl, and 2,3,4- trifluorobenzyl, said method comprising reacting the product of claim 8 wherein R, is H with 1,2 dichloroethane to form said further compound.

12. The method of claim 10 further comprising forming a further compound of said formula wherein R, is C 2 H 4 -OH, said method further comprising reacting the product of claim 8 wherein R, is H with O-butyryl glycoaldehyde to give a second reaction product; and further reacting said second reaction product with sodium methoxide to form said further compound. WO 02/072542 WO 02/72542PCTIUS02IO7033 00 98

13. The metho~d of claim 10 further comprising forming a further compound of said Ctformuha4vherein R, is acetyl comprising reacting the pouto li hri 1 i INDH with (N,N-dimethylamino)pyridine and acetic anhydride.

14. Tb'e method of claim 10 further comprising forming a further compound of said fonnula wherein R, and R 2 taken together are CH 2 -O-CH 2 comprising reacting the product of claim 8 wherein R, is H with 1,1'-carbonyldiimidazole and 4-(N,N- 00 dimethylamino)pyridine in benzene.

The method of claim 10 wherein R 3 is a para-substituent.

16. The method of claim 10 wherein R 3 is a meta-substituent.

17. A method of making or (R)-1-(2-methanesulphonamidephenoxy)-3-(3,4- dichlorophenylethylamino)-2-propanol) comprising the steps of: reacting 2-nitrophenol with or (R)-glycidyl nosylate to form or glycidyl o-nitrophenyl ether; reacting the product of step with 3,4-dichioropentylethylamine to form (S) or 1-(2-nitrophenyoxy)-3 ,4-dichlorophenylethylamino)-2-propanol; reacting the product of step with p-tolune-sulphonic acid and benzaldehyde to form 2 -phenyl-3(N-phenylethylamino)-5-(4-nitrophenoxy methyl)oxazolidime; reacting the product of step with sodium hydroxide to form 2-phenyl-3(N- phenylethylamino)-5-(4-aminophenoxy methyl)oxazolidine; and reacting the product of step with diisopropylamine and methansul fonyichioride to form 1 2 -methanesulphoneamidephenoxy)-3 dichiorophenylethylami no)-2-propanol. WO 02/072542 WO 02/72542PCT/US02/07033 00 99

18. A method for making or (R)-1I-(4-N-methyl-methanesulphonamidephenoxy)-3- (3 ,4-dichlorophenylethylamino)-2-propanoI comprising: reacting or (R)-blycidyl N-methylsulfonyl-p-aminophenyl ether with potassium carbonate and methyl iodide to form or (R)-glycidyl N-methyl- N-methanesulfonyl-p-aminophenyl ether; 00(b) reacting the product of step a) with 3,4-dichiorophenylethylamnine to form or 1 -(4-N-methyl -methanesulphonamidephenoxy)-3 dichlorophenylethylamino)-2-propanol.

19. A method for making or (R)-(1-(4-benzencsulphonamideophenoxy)-3-(3,4- dichloro-phenylethylamino)-2-propanol comprising reacting or (R)-glycidyl N- methylsulfonyl-aminophenyl ether with N,N-diisopropyl-N-ethylarnine to form or (R)-glycidyl N-benzenesulfonyl-p-aminophenyl ether, and reacting said ether with 3,4-dichiorophenylethylamine to form said or benzenesulphonamideophenoxy)-3 ,4-dichloro-phenylethylami no)-2-propanol. A method for making or (R)-1-(4-nitrophenoxy)3-(3,4- di chlorophenyl ethyl amino)-2-propanol comprising reacting p-nitrophenyl ether with 3 ,4-dichlrophenylethylamine to form said or 1 -(4-nitrophenoxy)3 dichlorophenylethylamino)-2-propanol.