Substituted .alpha.-amino acids having selected acidic moieties for use as excitatory amino acid antagonists in pharmaceuticals

The present invention is novel substituted .alpha.-amino acids, pharmaceutical compositions, methods of use, and preparations therefore having utility for treating disorders which benefit from blockade of aspartate and glutamate receptors.

BACKGROUND OF THE INVENTION 
Among excitatory amino acid receptor antagonists recognized for usefulness 
in the treatment of disorders are those that block N-methyl-D-aspartate 
(NMDA) receptors. 
For example, heterocycles containing nitrogen, and having phosphonic acid 
and carboxylate substituents, are found in European Application 
Publication Numbers 0159889 and 0203891 and Australian Application Number 
81455/87 which disclose utility for the treatment of nervous system 
disorders. The disorders disclosed which are responsive to blockade of the 
NMDA receptor include cerebral ischemia, muscular spasms (spasticity), 
convulsive disorders (epilepsy), and anxiety. These compounds, however, 
are readily distinguished from the compounds of the present invention both 
by the nitrogen containing heterocycles and by the various substituents 
thereon. 
Aliphatic .alpha.-amino acids are disclosed in British Patent Numbers 
2,104,078 and 2,156,818. The first of these, Number 2,104,078, includes 
2-amino-7-phosphonoheptanoic acid (APH) disclosed for use in treating 
Huntington's disease, Alzheimer's disease, and certain forms of epilepsy 
as well as for use in the prevention of brain damage associated with 
stroke (see SCRIP #1067, Jan. 13, 1986, page 22). The second of these, 
2,156,818, discloses usefulness for treating epilepsy, disorders 
associated with excess growth hormone (GH) or luteinizing hormone (LH) 
secretion, schizophrenia, depression, CNS degenerative disorders, and 
cerebral hypoxic conditions. 
More particularly, U.S Pat. No. 4,657,899 discloses compounds of the 
formula 
##STR1## 
wherein n and m=0, 1, 2, or 3 and X.sup.1 and X.sup.2 are the same or 
different and are selected from the group consisting of hydrogen, lower 
alkyl, halogen, --CH.dbd.CH--CH.dbd.CH--, amino, nitro, trifluoromethyl, 
or cyano, having activity as anticonvulsants, analgesics, and cognition 
enhancers through the antagonism of specific excitatory amino acid 
neurotransmitter receptors. 
U.S. Pat. No. 4,761,405 teaches a cycloalkyl ring system having 
substiluents similar to U.S Pat. No. 4,657,899. 
Additionally, .alpha.-amino acids on a carboxy-containing phenyl ring are 
disclosed in U.S. Pat. No. 4,065,572; British Patent Numbers 1,371,896 and 
917,435 and Canadian Patent Number 748,446. However, these disclosures 
have different substituents. 
The novel substituted .alpha.-amino acids of the present invention are not 
made obvious by these disclosures. In fact, clearly the disclosure of U.S. 
Pat. No. 4,657,899 is limited to a specific ortho positioning of 
phosphonic acid and amino acid residues on a phenyl ring. Such a 
limitation teaches away from the novel compounds of the present invention. 
An understanding of the role of excitatory amino acids is expanded by J. C. 
Watkins, et al, in "Recent Advances in the Pharmacology of Excitatory 
Amino Acids", Excitatory Amino Acid Transmission: Neurology and 
Neurobiology, 24:19-26, Ed by Hicks, Lodge and McLennan, Publisher: Alan R 
Liss, Inc , New York, 1987. 
An additional reference is now found to compounds, for example, for the 
treatment of diseases responding to a blockade of NMDA-sensitive 
receptors, in European Application Publication Number 0233154, of the 
formula 
##STR2## 
showing a basic difference in that the phosphorus containing substituent 
and the amino/carboxy containing substituent are linked through a straight 
chain double bonded C.dbd.C linkage and not as substituents on a common 
aryl ring. 
Then, on the other hand antagonists to the NMDA sensitive excitatory amino 
acid receptors are shown in U.S. Pat. No. 4,746,653, filed Feb. 28, 1986, 
to include substituted saturated pyridinyl ring systems common to both a 
phosphorus containing and carboxy or carboxy derivatized substituent. 
More recently, the British Patent Application Number 2,198,134, filed Oct. 
30, 1986, but not published before Jun. 8, 1988, teaches compounds useful 
for treating epilepsy including anticonvulsant activity shown from 
inhibition of NMDA in excitatory amino acid systems having the formula 
##STR3## 
wherein R.sub.1 is a carboxy or carboxy containing analogue and y is a 
##STR4## 
containing substiluent. However, the present invention is defined by a 
scope not taught within the broad disclosure of this application and, 
therefore, represents an advance not made obvious therein. 
Although a related reference teaches "The Synthesis of p-Substituted 
D,L-Phenylglycines by the Amidoalkylation of Benzylchloride and 
N-Benzylbenzamide", Tetrahedron 33:2715-7 (1977) by D. Ben-Ishai, et al, 
it does not make obvious the use of the process for phosphonate containing 
derivatives. 
Also known is the use of a 4-tetrazolylmethyl group on a 
piperidinyl-2-carboxylic acid moiety for use as an excitatory amino acid 
receptor antagonist as shown by a poster by Dr. P. L. Ornstein, et al, at 
the "First Princeton Drug Research Symposium" on May 21st to 23rd, 1989 
and as disclosed in European Patent Application Number 330,353. However, 
no teaching is disclosed for the present from the piperidine of Ornstein's 
poster. 
Finally, EP Publication Number 318935, a copending application, and 
European Patent Application Publication Number 313002 both disclose the 
use of a phosphonyl acid group. 
Not all piperidinyl, pyridinyl or other heterocyclic ring systems are 
included in this Background as it is deemed such systems are different 
from the present invention compounds. 
SUMMARY OF THE INVENTION 
The present invention is a novel compound selected from the formula (IA, IB 
or IC) 
##STR5## 
or a pharmaceutically acceptable acid addition or base salt thereof; 
wherein the group (I.sub.a) 
##STR6## 
is ortho, meta or para to the group (I.sub.b, I.sub.c or I.sub.d) 
##STR7## 
wherein (1) n is 0, 1, or 2; 
(2) R.sup.5 is independently hydrogen or a pharmaceutically acceptable 
labile ester residue; 
(3) R.sup.3 and R.sup.4 are independently hydrogen, hydroxy, lower alkyl, 
aryl, arylalkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, 
lower alkoxy-methyl, or taken together with adjacent ring carbons are 
--CH.dbd.CH--CH.dbd.CH--; 
(4) R.sup.9 is hydrogen or a protecting group; 
(5) Q is --(CH.sub.2).sub.m --, --(CH.dbd.CH)--, --CH.sub.2 
--(CH.dbd.CH)--, or (CH.dbd.CH)--CH.sub.2 -- wherein m is 0, 1, 2, or 3 
with the proviso that in the formula IA m cannot be 0 when Z is CO.sub.2 
R.sup.20 and both R.sup.3 and R.sup.4 are hydrogen, and also in the 
formula IA the m cannot be 0 when Z is CO.sub.2 R.sup.20 and R.sup.3 is 
hydrogen and R.sup.4 is alkyl or hydroxy or lower alkoxy or halogen; 
(6) Z.sub.a is selected from 
(a) --PO.sub.2 R.sup.20 R.sup.21 wherein R.sup.20 and R.sup.21 are 
independently selected from hydrogen, lower alkyl, lower alkenyl, aryl, 
aryl lower alkyl, or a pharmaceutically acceptable labile ester group, 
(b) --CO.sub.2 R.sup.20 wherein R.sup.20 is as defined above, or 
##STR8## 
Z.sub.b is PO.sub.3 R.sup.20 R.sup.21 wherein R.sup.20 and R.sup.21 are as 
defined above; n is 0 or 1 and m is 0, 1, or 2; and R.sup.3 or R.sup.4 are 
hydroxy; 
Z is PO.sub.3 R.sup.20 R.sup.21, PO.sub.2 R.sup.20 R.sup.21, CO.sub.2 
R.sup.20 or 
wherein R.sup.20 and R.sup.21 are as defined above. 
Preferably the compounds of formula IA and IB are limited so that when the 
group I.sub.a is para to the group I.sub.b then n may be 0 is 0, 1, 2, or 
3 and n may be 1 when m is 0 or 2; that when the group I.sub.a is meta to 
the group I.sub.b or I.sub.c then n may be 0 when m is 1 or 2, n may be 1 
when m is 0, 1, or 2, and n may be 2 when m is 0; and that when group 
I.sub.a is ortho to group I.sub.b or I.sub.c then n may be 1, when m is 1, 
2, and 3. 
More preferred are the compounds IA and IC wherein Z.sub.a and Z are 
respectively CO.sub.2 R.sup.2 or 
##STR9## 
An additional aspect of the present invention is a compound selected from 
the formula 
##STR10## 
wherein n, Z, R.sup.5, and R.sup.9 are as defined above and preferred 
compounds of ID and IE have the group 
##STR11## 
para to Z when n is 0 or 1 or meta to Z when n is 1 or 2. 
Again, more preferred of the compounds of ID or IE are those where Z is 
CO.sub.2 R.sup.2 or 
##STR12## 
The present invention is also a pharmaceutical composition for the 
treatment of cerebrovascular disorders in which excitatory amino acid 
antagonists are useful comprising an amount effective to block glutamate 
or aspartate (NMDA) receptors of a compound of the formula 1 as defined 
above and a pharmaceutically acceptable carrier. 
Such disorders include cerebral ischemia or cerebral infarction, resulting 
from a range of conditions, such as thromboembolic or hemorrhagic stroke, 
cerebral vasospasm, hypoglycemia, cardiac arrest, and status epilepticus, 
and also include schizophrenia, epilepsy, neurodegenerative disorders, 
Alzheimer's disease, or Huntington's disease. They are also useful as 
analgesics Further, cerebrovascular damage may be treated prophylactically 
or therapeutically where a finite risk of the damage is understood to be 
present by an ordinarily practicing physician, such as in surgical 
procedures. 
Thus, further the present invention is a method of treating cerebrovascular 
disorders particularly in which amino acid antagonists are useful in a 
human suffering therefrom or at risk of such disorders which comprises 
administering a compound of the formula I as defined above in a unit 
dosage form. 
Finally, the present invention is also novel processes. In the processes a 
compound of formula IA, IB, and ID are hereinafter referred to as the 
compound of formula I for convenience. 
One of the novel processes is for the preparation of a compound of formula 
I wherein n is 0 and m is 1, 2, or 3 as defined above which comprises 
Step (1) reacting a compound of the formula (X) 
##STR13## 
wherein R.sup.5.sub.a is R.sup.5 but not including hydrogen and R.sup.7 is 
an acid stable protective group, such as a benzoyl, benzyloxycarbonyl, or 
ethoxycarbonyl; 
with a compound of the formula Xl 
##STR14## 
wherein m.sub.a is 1, 2, or 3, X is CO.sub.2 H, chloro or bromo, and 
R.sup.3 and R.sup.4 are as defined above; 
in the presence of methanesulfonic acid or strongly dehydrating acids such 
as concentrated sulfuric acid over a period of forty-eight hours at room 
temperature to obtain a compound of the formula XII 
##STR15## 
wherein R.sup.3, R.sup.4, R.sup.5.sub.a, and R.sup.7 are as defined above 
when one of R.sup.3 and R.sup.4 are not H then R.sup.3 and R.sup.4 may be 
a group whose regiochemical direction influence is compatible with this 
reaction. Selection of such groups would be apparent to one of ordinary 
skill in the art. 
Step (2) the compounds of the formula XII are then treated with a compound 
of the formula (XlII) 
EQU R.sup.8 Z.sup.1 XIII 
wherein R.sup.8 is sodium, potassium, or the like and Z.sup.1 is --CN, 
--PO.sub.3 R.sup.20 R.sup.21 or --PO.sub.2 R.sup.20 R.sup.21, wherein 
R.sup.20 and R.sup.21 are as defined above except that where required each 
may be a protecting group such as when the R.sup.20 functions as a 
precursor to a hydrogen; 
in a solvent such as tetrahydrofuran, diethyl ether, dimethylformamide, 
acetonitrile, or the like at temperatures from room temperature to reflux 
over a period of one to forty-eight hours to obtain the compound of the 
formula (XIV) (alternatively the phosphinoalkyl derivatives of formula XIV 
can be obtained by an Arbuzov reaction with phosphinate or an equivalent). 
##STR16## 
wherein R.sup.3, R.sup.4, Z.sup.1, R.sup.7, R.sup.5.sub.a, and m.sub.a are 
as defined above; 
The compounds of the formula XIV may be treated to remove protective 
groups, to protonate the acidic residues or to esterify the acid groups, 
if desired. 
This process is summarized in Scheme A as follows: 
##STR17## 
In another process of the present invention analogous to known processes 
the compounds of the formula I wherein groups I.sub.a and I.sub.b are 
meta, n is 0, and m is 1 is prepared in a process which comprises 
Step (1) reaction of a compound of the formula (XX) 
##STR18## 
wherein L is a leaving group such as halogen, e.g., I, Br, or Cl or a 
methanesulfonate, toluenesulfonate, or trifluoroacetate and one 
L-containing group is meta or para to the other L, and R.sup.3 and R.sup.4 
are as defined above; 
with a compound of the formula (XXI) 
EQU R.sup.8 Z.sup.1 XXI 
wherein R.sup.8, is as defined above and Z is --PO.sub.2 R.sup.20 R.sup.21, 
PO.sub.3 R.sup.20 R.sup.21 or --CN; 
in a solvent such as diethyl ether, tetrahydrofuran, dimethylformamide, or 
dimethoxyethane, and the like to obtain a compound of the formula (XXII) 
##STR19## 
wherein R.sup.3, R.sup.4, and L are all as defined above; 
Step (2) Sodium methoxide in methanol or sodium ethoxide in ethanol or the 
like is treated with 2-nitropropane and the compound of formula XXII to 
obtain a compound of the formula (XXIII) 
##STR20## 
Step (3) the compound of formula (XXIIIa wherein Z.sup.1 is CN) 
##STR21## 
wherein the CHO is protected and is treated either in a manner analogous 
to the processes of British Patent Number 2,104,078A to obtain a compound 
of the formula 
##STR22## 
or is treated with NaN.sub.3 and NH.sub.4 Cl in a solvent such as 
N-methylpyrrolidinone (NMP), or dimethylformamjde (DMF) at a temperature 
of from about 150.degree. C. to 200.degree. C. or treated with Bu.sub.3 
SnN.sub.3 in a manner similar to that described in EP 330,353 or as 
described in J. Organometallic Chem. 33:337-346 (1971) to obtain a 
compound of the formula 
##STR23## 
wherein R.sup.10 is H or SnBu.sub.3 (wherein Bu is butyl) 
Step (3) the compound of formula XXIII, wherein the CHO is no longer 
protected wherein Z is PO.sub.3 R.sup.20 R.sup.21, PO.sub.2 R.sup.20 
R.sup.21, COOH, or tetrazolyl, is then stirred in a solution of sodium 
metabisulfite in water to which concentrated ammonium hydroxide is then 
added followed by the addition of NaCN to obtain a compound of the formula 
(XXIV) 
##STR24## 
wherein Z is as defined above; 
Step (4) the compound of the formula XXIV may be hydrolyzed, if necessary, 
to obtain the compound of formula I wherein R.sup.3 and R.sup.4 is as 
defined above and R.sup.5 is hydrogen and optionally treated further to 
obtain the formula I wherein R.sup.20, R.sup.21, and R.sup.5 are a desired 
ester or amide residue or pharmacologically acceptable base salt thereof. 
This process is summarized in Scheme B as follows: 
##STR25## 
Another process to prepare the compounds of the present invention of 
formula I wherein one halogen containing group is ortho, meta or para to 
the other halogen and n is 1 and m is 1 is analogous to that of U.S. Pat. 
No. 4,657,899 and is shown as follows in Scheme C. Optionally, products of 
this scheme can also be further reacted to obtain desired salts or labile 
esters or amides thereof. 
##STR26## 
Another process of the present invention is for the preparation of 
compounds of the formula I wherein groups I.sub.a and I.sub.b are para, 
meta or ortho; n is 0; and m is 2 which comprises 
Step (1) treating a compound of the formula (XXX) 
##STR27## 
wherein Y is Br, I or OSO.sub.2 CF.sub.3, R.sup.3 and R.sup.4 are as 
defined above; 
in a solvent such as ethanol, methanol, and the like with ammonium chloride 
in water, then a solution of potassium cyanide also in water is added 
after which the product is treated with HCl in ether to obtain the 
compound of formula (XXXI) 
##STR28## 
which is treated to add a protecting group to the amino substituent; 
Alternatively, the compound of formula XXXI is treated to convert CN to an 
ester group before treating with a compound of formula XXXII; 
Step (2) the protected compound of formula XXXI wherein Y is Br, I or 
OSO.sub.2 CF.sub.3 is then treated with a compound of the formula (XXXII) 
EQU H.sup.2 C.dbd.CHZ.sup.2 XXXII 
wherein Z.sup.2 is CN, COOR.sup.20, PO.sub.3 R.sup.20 R.sup.21, PO.sub.2 
R.sup.20 R.sup.21 ; or 
##STR29## 
in the presence of palladium acetate, tri-orthotolylphosphine and 
tri-n-butylamine in a solvent such as xylene, toluene, and the like to 
obtain the compound of the formula (XXXIII) 
##STR30## 
wherein R.sup.10 is a protecting group an Z.sup.2, R.sup.3, and R.sup.4 
are as defined above; 
In the instance where Z.sup.2 in the compound of formula XXXIII is CN, the 
compound may be treated with NaN.sub.3 and NH.sub.4 Cl in DMF or NMP or as 
illustrated in EP 330,353 or the J. Organometallic Chem. 33:337-346 
(1971), to obtain the compound of formula (XXXIII.sub.a) 
##STR31## 
Step (3) then the compound of formula XXXIII or XXXIII.sub.a is optionally 
hydrogenated and then hydrolyzed or hydrolyzed to obtain the compound of 
formula 1. 
This process is summarized in Scheme D as follows: 
##STR32## 
Variations in this sequence of treatment is within the skill of an ordinary 
artisan. 
Another process of the present invention to prepare the compounds of the 
present invention of the formula I wherein groups I.sub.a and I.sub.b are 
ortho, meta or para and wherein n is 1 and m is 2 comprises 
Step (1) treating a compound of the formula XL 
##STR33## 
wherein L, R.sup.3, and R.sup.4 are as defined above with 
diethylacetamidomalonate, dimethylacetamidomalonate, 
diethylformamidomalonate, or the like in the presence of sodium ethoxide 
in ethanol or sodium methoxide in methanol or the like to obtain a 
compound of the formula XLI. 
##STR34## 
wherein R.sup.10 is as defined above and Et is ethyl; 
Step (2) the compound of formula XLI is treated in a manner analogous to 
Steps (2) and (3) in Scheme D above to obtain the compound of formula I 
wherein n is 1 and m is 2; 
Additionally, alternative methods can be shown for Step (2) providing 
various compounds of the invention wherein n is 1 and m is 0 as follows: 
Step (2), the product of Step (1), compound of formula XLI, is treated with 
HPO.sub.3 (C.sub.2 H.sub.5).sub.2, HPO.sub.2 (C.sub.2 H.sub.5)R.sub.20 or 
CO plus methanol in a palladium catalyzed exchange of the Br, I, OSO.sub.2 
CF.sub.3 substituent using conditions analogous to those found in 
Synthesis, 56-57 (1981). 
Step (2) Alternatively, the product of Step (1), compound of the formula 
XLI, is treated with CuCN in DMF at temperatures between 150.degree. C. to 
220.degree. C. or by other methods known to those skilled in the art such 
as those described in Chem. Rev. 87:779-779 (1987) and J. Chem. Soc. 
Perkin I 1365 (1989). 
Step (3) Each of the above Step (2) is followed by hydrolysis with optional 
treatment to obtain a compound of the formula (XLII) 
##STR35## 
wherein R.sup.3, R.sup.4, R.sup.5, and Z are as defined above. 
The substituent Br(I or OSO.sub.2 CF.sub.3) may also be meant to include 
equivalents selected by one of ordinary skill in the art including, for 
example, mercuric halides, and the like. (See Heck, Richard F., Palladium 
Reagents in Organic Synthesis, Academic Press (1985)). 
Again, variations to react intermediates having the substituents Br(I or 
OSO.sub.2 CF.sub.3) to obtain CH.sub.2 CN and then further to obtain 
CH.sub.2 CO.sub.2 H or can be accomplished in the same manner as set out 
above using appropriate analogous reaction conditions. 
These various process steps can be shown as follows in Scheme E. 
##STR36## 
Finally, the present invention is a process for the preparation of a 
compound of the formula I wherein n is 2 and m is 0, comprising 
Step (1) treating a compound of the formula (LX) 
##STR37## 
with bistrifluoromethanesulfonyl aniline of the formula 
##STR38## 
in methanol in the presence of diisopropylethylamine using conditions 
analogous to those described in J. Am. Chem. Soc. 109(9):2381 (1987) to 
obtain a compound of the formula (LXI) 
##STR39## 
wherein Tf is the triflate residue; 
Step (2) the compound of the formula LXI is then treated with a compound of 
the formula HZ.sup.2 wherein Z.sup.2 is as defined above in the presence 
of a palladium catalyst as described in J. Am. Chem. Soc. 109(9):2381 
(1987) or, alternatively, the triflate provides the substituent which can 
be converted to CH.sub.2 CN and then either CH.sub.2 CO.sub.2 H or 
##STR40## 
to obtain a compound of the formula (LXII) 
##STR41## 
The compound of formula LXII can be treated in a manner known, or analogous 
to known processes, to obtain compounds of formula I wherein n is 2 and m 
is 0, having the desired ester or salt. 
Also among the novel processes for the preparation of the compounds of 
Formula I wherein n is 0 and m is 1 as defined above are the following: 
A process for preparing the compound of the Formula I wherein R.sup.3 and 
R.sup.4 are hydrogen, Q is --CH.sub.2 -- is and Z is --COOH comprises (1) 
reacting the compounds of formula 
##STR42## 
with a compound of the formula 
##STR43## 
in a manner similar to that described in Scheme A, Step 1, obtain the 
compound having a protected amine group of the formula 
##STR44## 
For purposes of purification, the compound of formula 3 may be esterified 
with CH.sub.2 N.sub.2 at about -40.degree. C. to +35.degree. C. preferably 
25.degree. C. for from 5 to 45 minutes, preferably 15 minutes to obtain a 
compound of the formula 
##STR45## 
which may then be treated with acid such as 6N HCl at reflux until the 
desired product of the formula 
##STR46## 
is obtained. 
On the other hand a process for preparing a compound of the formula I 
wherein one of R.sup.3 and R.sup.4 is hydrogen and the other of R.sup.3 
and R.sup.4 is hydroxy at the position para to the amin acid containing 
substituent and the COOH group meta to the amine substituent comprises (1) 
treating a compound of the formula 
##STR47## 
with a protected hydrox-vhippuric acid in the presence of formic acid to 
obtain the compound of the formula 
##STR48## 
wherein Ph is phenyl; 
As an optional step to aid purification, the compound of Formula 3 may be 
treated with an alkanol such as methanol, ethanol or the like in an acid 
medium to obtain the compound of the formula 
##STR49## 
wherein Ph is as defined above, Et is ethyl and Me is methyl; and 
following purification, then treating with an acid, such as 6N HCl the 
compound of the Formula 6 (see Scheme F) to obtain the compound free of 
protecting groups having the formula 
##STR50## 
A process for preparing the compound of the formula I wherein one of 
R.sup.3 and R.sup.4 is an OH in a position ortho to the group containing 
the COOH that is para to the amino acid containing group comprised 
(1) treating a compound of the Formula 
##STR51## 
with acetic anhydride to obtain a compound showing an alternative 
protecting group on the amino substituent of the formula 
##STR52## 
wherein Ac is acetyl 
(2) treating the compound of the formula 8 with CH.sub.2 N.sub.2 to 
esterify the COOH for protecting it yielding a compound of the formula 
##STR53## 
wherein Me is methyl and Ac is acetyl; 
(3) treating the compound of the formula 9 with allyl bromide in the 
presence of K.sub.2 CO.sub.3 in a solvent such as acetone to obtain the 
compound of the formula 
##STR54## 
wherein Me is methyl and Ac is acetyl; 
(4) reacting the compound of the formula 10 in p-dichlorobenzene at about 
350.degree. C. to obtain the compound of the formula 
##STR55## 
wherein Me is methyl and Ac is acetyl; 
(5) treating the compound of the formula 11 with benzoyl chloride in a 
solvent system such as chloroform and triethylamine or pyridine to obtain 
the compound 
##STR56## 
wherein Ph is phenyl, Me is methyl, and Ac is acetyl; 
(6) treating the compound of the formula 12 with sodium metaperiodate and 
RuCl.sub.3 in a solvent system such as H.sub.2 O, CH.sub.3 CN or 
benzonitrile and CCl.sub.4 at about +5.degree. C. to +40.degree. C., 
preferably 25.degree. C. to obtain the compound of the formula 
##STR57## 
wherein Ph is phenyl, Me is methyl, and Ac is acetyl; 
(7) the compound of the formula 13 may be treated by refluxing in acidic 
medium such as 6N HCl to obtain the compound of the formula 
##STR58## 
A process for preparing a compound of formula I wherein Q is CH.sub.2, Z is 
tetrazole, and one of R.sup.3 and R.sup.4 is OH ortho to the tetrazole 
containing substituent comprises (1) treating a compound of the formula 12 
as defined above in a solvent such as dichloromethane with ozone followed 
by treating with dimethylsulfide to obtain the compound of the formula 
##STR59## 
wherein Ph is phenyl and Me is methyl; 
(2) treating the compound of the formula 14 with 
O,N-bistrifluoroacetylhydroxylamine in a solvent such as toluene in the 
presence of pyridine to obtain the compound of the formula 
##STR60## 
wherein Ph is phenyl and Me is methyl; 
(3) treating the compound of formula 15 in a solvent such as dioxane with 
tri-n-butyltinazide to obtain the compound of the formula 
##STR61## 
wherein Ph is phenyl and Me is methyl; 
(4) again the penultimate compound of formula 16 may be treated at reflux 
with an acidic medium such as 6N HCl to obtain the desired compound of the 
formula 
##STR62## 
These reactions for compounds I.sub.1, I.sub.2, I.sub.3, and I.sub.4 are 
summarized in Schemes F, G, and H as follows: 
##STR63## 
Compounds of the formula I wherein Z is a tetrazolyl may alternatively be 
prepared by methods analogous to those described in J. Orqanometal. Chem. 
33;337-346 (1971). 
A process including the following steps (1) to (10) for which the sequence, 
i.e., order, is critical for the preparations of the compound of the 
formula I wherein one of R.sup.3 and R.sup.4 is hydrogen and the other is 
an OH in a position ortho to the group containing a PO.sub.3 H.sub.2 that 
is para to the amino acid containing group comprises 
(1) treating a compound of the formula 
##STR64## 
with CH.sub.2 H.sub.2 to esterify the COOH for protecting it, yielding a 
compound of the formula 
##STR65## 
wherein Me is methyl; 
(2) treating the compound of the formula 17 with a trialkylsilyl halide 
such as tert-butyldimethylsilyl chloride, trimethylsilyl chloride or 
dimethylthexylsilyl chloride, preferably tert-butyldimethylsilyl chloride 
in the presence of a trialkylamine such as triethylamine at room 
temperature in a solvent such as methylenechloride to obtain a compound of 
the formula 
##STR66## 
wherein Me is methyl and R.sub.19 is corresponding alkylsilyl (this step 
introduces a blocking group to hinder ring bromination in the following 
step); 
(3) treating the compound of formula 19 with a free radical halogenating 
reagent such as N-bromosuccinamide in the presence of a free radical 
catalyst such as AIBN (azabisisobutyronitrile) in a solvent system such as 
carbontetrachloride near a source of light such as a high intensity light 
bulb to obtain the compound of the formula 
##STR67## 
wherein Me is methyl and R.sub.19 is the corresponding alkylsilyl group as 
above; 
(4) treating the compound of formula 20 with a solution of a hydride 
reducing agent such as lithium aluminum hydride, sodium borohydride, or 
diisobutyl-aluminum hydride or the like, preferably diisobutyl aluminum 
hydride in a solvent system such as tetrahydrofuran, diethylether or 
toluene or the like, at about -78.degree. C. followed by rapid addition of 
a saturated aqueous potassium-sodium tartrate solution to the reaction 
mixture at -78.degree. C. to avoid decomposition of the product so there 
is obtained the compound of the formula 
##STR68## 
wherein Me is methyl and R.sub.19 is the corresponding alkylsilyl as set 
out above; 
(5) treating the compound of the formula 21 with a trialkyl silyl halide 
such as tert-butyldimethylsilyl chloride, trimethylsilyl chloride, 
dimethylthexysilyl chloride in the presence of a trialkylamine such as 
triethylamine and an amine containing catalyst such as 
N,N-dimethylaminopyridine at room temperature in a solvent such as 
methylene chloride to obtain a compound of the formula 
##STR69## 
wherein Me is methyl, Et is ethyl, and R.sub.19 and R.sub.22 are 
respective corresponding alkylsilyl; 
(6) treating the compound of the formula 22 with a trialkylphosphite such 
as triethylphosphite at about 75.degree. C. to 150.degree. C. preferably 
at 114.degree. C. to obtain the compound of the formula 
##STR70## 
wherein Me is methyl, Et is ethyl, and R.sub.19 and R.sub.22 are 
corresponding alkylsilyl; 
(7) treating the compound of the formula 23 with a dilute aqueous acid, 
preferably 1N HCl, in a solvent such as methanol or ethanol at about 
-20.degree. C. to 20.degree. C., preferably 0.degree. C., to obtain the 
compound of the formula 
##STR71## 
wherein Me is methyl, Et is ethyl, and R.sub.19 is the corresponding 
alkylsilyl and set out above; 
(8) treating the compound of the formula 24 with oxalylchloride and 
dimethylsulfoxide in the presence of triethylamine in methylenechloride at 
about -70.degree. C. to 0.degree. C. or by other methods known to those 
skilled in the art to obtain the compound of the formula 
##STR72## 
wherein Me is methyl, Et is ethyl, and R.sub.19 is the corresponding 
alkylsilyl as set out above; 
(9) treating the compound of the formula 25 with zinc iodide and a 
trialkylsilylcyanide such as trimethylsilylcyanide at room temperature in 
a solvent such as methylenechloride followed by treatment with methanol 
saturated with ammonia gas with heating to about 40.degree. C. to obtain 
the compound of the formula 9 
##STR73## 
wherein Me is methyl, Et is ethyl, and is the corresponding alkylsilyl as 
set out above; 
(10) the compound of the formula 26 may be deprotected by refluxing in 
acidic medium such as 6N HCl to obtain the compound of the formula 
##STR74## 
Finally, the compounds of formula IC and IE are prepared from the compounds 
of the formula IA, IB or ID having corresponding substituents using 
methods analogous either to those described in U.S. Pat. No. 4,761,405 by 
RhCl.sub.3 .multidot.3H.sub.2 O in the presence of NaBH.sub.4 in ethanol 
at about 30.degree. C. or, in the alternative, by hydrogenation with about 
50 psi of hydrogen in methanol or acetic acid using a 10% rhodium on 
carbon catalyst Although final stereochemistry is assumed to be 
predominantly cis, the trans isomers are also within the scope of the 
invention.

DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of formula I the term "lower alkyl" is meant to include a 
straight or branched alkyl group having one to four carbon atoms, such as, 
for example, methyl, ethyl, propyl, or butyl, and isomers thereof. 
Pharmaceutically acceptable labile ester residues within the context of the 
present invention represents an ester residue of the esterified carboxy 
group I.sub.a or "esterified phosphono" group I.sub.b above, preferably a 
carboxylic acid or phosphono acid prodrug ester that may be convertible 
under physiological conditions to free carboxy or phosphono acid groups. 
That is, the pharmaceutically acceptable esterified carboxy of the group 
I.sub.a preferably represent e.g., lower alkoxycarbonyl; (amino, mono-,or 
di-lower alkylamino)- substituted straight chain lower alkoxycarbonyl, 
carboxy substituted lower alkoxycarbonyl, e.g., 
.alpha.-carboxy-substituted lower alkoxycarbonyl; lower 
alkoxycarbonyl-substituted lower alkoxycarbonyl, e.g., .alpha.-lower 
alkoxycarbonyl-substituted lower alkoxycarbonyl; aryl-substituted lower 
alkoxycarbonyl, e.g., unsubstituted or substituted benzyloxyoarbonyl or 
pyridylmethoxycarbonyl; lower alkanoyloxy-substituted methoxycarbonyl, 
e.g., pivaloyloxymethoxycarbonyl; (lower alkanoyloxy or lower 
alkoxy)-substituted lower alkoxymethoxycarbonyl; bicyclo[2.2.1] 
heptyloxycarbonyl-substituted methoxycarbonyl, e.g. 
bornyloxycarbonyl-methoxycarbonyl; 3-phthalidoxycarbonyl; (lower alkyl, 
lower alkoxy, halo)-substituted 3-phthalidoxycarbonyl; lower 
alkoxycarbonyloxy-lower alkoxycarbonyl; e.g., 1-(methoxy- or 
ethoxycarbonyloxy)-ethoxycarbonyl. 
Most preferred prodrug esters are e.g., the straight chain C.sub.1-4 -alkyl 
esters, e.g., ethyl; the lower alkanoyloxymethyl esters, e.g., 
pivaloyloxymethyl; the di-lower alkylamino-straight chain C.sub.2-4 -alkyl 
esters, e.g., 2-diethyl-aminoethyl; the pyridylmethyl esters, e.g., 
3-pyridylmethyl. 
The labile amide residues of either the carboxy or phosphono substituent 
may include those amides known by artisans to be useful as prodrugs. 
Lower alkoxy is -O-alkyl or of from one to four carbon atoms as defined 
above for "lower alkyl". 
Lower alkylthio is -S-alkyl of from one to four carbons. 
Appropriate compounds of formula I are useful in the free base form, in the 
form of base salts where possible, and in the form of acid addition salts. 
The three forms are within the scope of the invention. In practice, use of 
salt form amounts to use of the base form. Pharmaceutically acceptable 
salts within the scope of the invention are those derived from mineral 
acids such as hydrochloric acid and sulfuric acid; and organic acids such 
as ethanesulfonic acid, benzene-sulfonic acid, p-toluenesulfonic acid, and 
the like, giving the hydrochloride, sulfonate, ethanesulfonate, 
benzenesulfonate, p-toluenesulfonate, and the like, respectively, or those 
derived from bases such as suitable organic and inorganic bases. Examples 
of pharmaceutically acceptable base addition salts with compounds of the 
present invention include organic bases which are nontoxic and strong 
enough to form such salts. These organic bases form a class whose limits 
are readily understood by those skilled in the art. Merely for purposes of 
illustration, the class may be said to include mono-, di-, and 
trialkylamines, such as methylamine, dimethylamine, and triethylamine; 
mono-, di-, or trihydroxyalkylamines such as mono-,di-, and 
triethanolamine; amino acids such as arginine, and lysine; guanidine; 
N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; 
morpholine; ethylenediamine; N-benzylphenethylamine; 
tris(hydroxymethyl)aminomethane; and the like. (See for example, 
"Pharmaceutical Salts," J. Pharm. Sci. 66(1):1-19 (1977).) 
The acid addition salts of said basic compounds are prepared either by 
dissolving the free base of compound I in aqueous alcohol solution or 
other suitable solvents containing the appropriate acid or base and 
isolating the salt by evaporating the solution, or by reacting the free 
base of compound I with an acid as well as reacting compound I having an 
acid group thereon with a base such that the reactions are in an organic 
solvent, in which case the salt separates directly or can be obtained by 
concentration of the solution. 
The compounds of the invention contain one or more asymmetric carbon atoms. 
Thus, the invention includes the individual stereoisomers, and mixtures 
thereof. The individual isomers may be prepared or isolated by methods 
known in the art. 
One of skill in the art would recognize variations in the sequence and 
would recognize appropriate reaction conditions from analogous reactions 
which may be appropriately used in the processes to make the compounds of 
formula I herein. Further, the starting materials are known or can be 
prepared by known methods. 
Under certain circumstances it is necessary to protect the nitrogen atom of 
intermediates in the above noted process with suitable protecting groups 
which are known. Introduction and removal of such suitable nitrogen 
protecting groups are well-known in the art of organic chemistry; see for 
example, "Protective Groups in Organic Chemistry," J. F. W. McOmie, ed., 
(New York, 1973), pages 43 ff, 95 ff, J. F. W. McOmie, Advances in Organic 
Chemistry 3:191-281 (1963); R. A. Borssona, Advances in Organic Chemistry 
3:159-190 (1963); and J. F. W. McOmie, Chem. & Ind. 603 (1979). 
In the process described herein for the preparation of compounds of this 
invention the requirements for protective groups are generally well 
recognized by one skilled in the art of organic chemistry, and accordingly 
the use of appropriate protecting groups is necessarily implied by the 
processes of the charts herein, for example, the protecting groups must be 
stable to the conditions of the processes, although not expressly 
illustrated. 
Starting materials for the processes described above are known or can be 
prepared by known processes. 
The products of the reactions described herein are isolated by conventional 
means such as extraction, distillation, chromatography, and the like. 
The salts of the compounds of formula I described above are prepared by 
reacting the appropriate base or acid with a stoichiometric equivalent of 
the compounds of formula I, respectively, to obtain pharmaceutically 
acceptable salts thereof. 
The preferred compounds of the present invention are of the formula I 
wherein when the groups I.sub.a to I.sub.b or I.sub.a to I.sub.c are in a 
meta relationship then n is 1 and m is 1 or 2 and also then n is 2 and m 
is 0; when the groups I.sub.a to I.sub.b or I.sub.a to I.sub.c are in a 
para relationship then n is 0 and m is 1; or when the groups I.sub.a to 
I.sub.b and I.sub.a to I.sub.c are in an ortho relationship then n is 1 
and m is 2. 
The more preferred compounds of the present invention are of the formula I 
having the limitations of the preferred compounds but further have R.sup.3 
and R.sup.4 selected from hydrogen or hydroxy, particularly in the 
position ortho to the substituent having the Z group. 
Additionally, the compounds having the limitations of the more preferred 
compounds and additionally having Z defined as the COOR.sup.5 or 
##STR75## 
are the most preferred compounds. 
The activity of the compounds of the formula I is shown in vitro in an NMDA 
receptor binding assay based on the use of [.sup.3 H]CPP as antagonist 
ligand in a manner essentially as set out by B. E. Murphy, et al, in J. 
Pharm. Exp. Ther. 240:778 (1987). Examples I.sub.1, I.sub.2, and I.sub.3 
all exhibit CPP binding activity of IC.sub.50 better than 100 .mu.M. 
The compounds of the present invention can be shown to be antagonists as 
inhibitors of [.sup.3 H]TCP tissue binding in an in vitro assay described 
in Eur. J. Pharmacol. 123:467 (1986) and Neurosci. Lett. 76:221 (1987) or 
as inhibitors of glutamate stimulated acetylcholine release from striatal 
slice preparations as disclosed in J. Pharm. Exp. Ther. 240:737 (1987). 
In vivo activity for the compounds of the present invention is shown by 
selected compounds in the assays of EP Publication Number 318935, 
incorporated herein by reference, which are generally accepted to 
establish the utility for the treatment of diseases as noted above. 
Therefore, the compounds of formula I and their pharmacologically 
acceptable acid addition salts are effective agents in the prophylaxis 
and/or therapeutic treatment of disorders responsive to agents which block 
NMDA receptors, thus forming a further aspect of the present invention in 
like manner. 
For medical use, the amount required of a compound of formula I or 
pharmacologically acceptable salt thereof (hereinafter referred to as the 
active ingredient) to achieve a therapeutic effect will, of course, vary 
both with the particular compound, the route of administration and the 
mammal under treatment and the particular disorder or disease concerned. A 
suitable systemic dose of a compound of formula I or pharmacologically 
acceptable salt thereof for a mammal suffering from, or likely to suffer 
from any condition as described hereinbefore is in the range 0.01 to 100 
mg of base per kilogram body weight, the most preferred dosage being 0.05 
to 50 mg/kg of mammal body weight. 
It is understood that the ordinarily skilled physician or veterinarian will 
readily determine and prescribe the effective amount of the compound for 
prophylactic or therapeutic treatment of the condition for which treatment 
is administered. In so proceeding, the physician or veterinarian could 
employ an intravenous bolus followed by intravenous infusion and repeated 
administrations, parenterally or orally, as considered appropriate. 
While it is possible for an active ingredient to be administered alone, it 
is preferable to present it as a formulation. 
Formulations of the present invention suitable for oral administration may 
be in the form of discrete units such as capsules, cachets, tablets, or 
lozenges, each containing a predetermined amount of the active ingredient; 
in the form of a powder or granules; in the form of a solution or a 
suspension in an aqueous liquid or nonaqueous liquid; or in the form of an 
oil-in-water emulsion or a water-in-oil emulsion. The active ingredient 
may also be in the form of a bolus, electuary, or paste. 
A tablet may be made by compressing or molding the active ingredient 
optionally with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing, in a suitable machine, the active ingredient 
in a free-flowing form such as a powder or granules, optionally mixed with 
a binder, lubricant, inert diluent, surface active, or dispersing agent. 
Molded tablets may be made by molding, in a suitable machine, a mixture of 
the powdered active ingredient and a suitable carrier moistened with an 
inert liquid diluent. 
Formulations suitable for parenteral administration conveniently comprise a 
sterile aqueous preparation of the active ingredient which is preferably 
isotonic with the blood of the recipient. 
Formulations suitable for nasal or buccal administration, (such as 
self-propelling powder dispensing formulations described hereinafter), may 
comprise 0.1 to 20% w/w, for example 2% w/w of active ingredient. 
The formulations, for human medical use, of the present invention comprise 
an active ingredient in association with a pharmaceutically acceptable 
carrier therefor and optionally other therapeutic ingredient(s). The 
carrier(s) must be `acceptable` in the sense of being compatible with the 
other ingredients of the formulations and not deleterious to the recipient 
thereof. 
So the pharmacologically active compounds of the invention are useful in 
the manufacture of pharmaceutical compositions comprising an effective 
amount thereof in conjunction or admixture with excipients or carriers 
suitable for either enteral or parenteral application. Preferred are 
tablets and gelatin capsules comprising the active ingredient together 
with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, 
cellulose, and/or glycine; b) lubricants, e.g. silica, talcum, stearic 
acid, its magnesium or calcium salt, and/or polyethyleneglycol; for 
tablets also; c) binders e.g. magnesium aluminum silicate, starch paste, 
gelatin, tragacanth, methylcellulose, sodium carboxymethyl-cellulose 
and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, 
agar, alginic acid, or its sodium salt, or effervescent mixtures; and/or 
e) absorbents, colorants, flavors, and sweeteners. Injectable compositions 
are preferably aqueous isotonic solutions or suspensions, and 
suppositories are advantageously prepared from fatty emulsions, or 
suspensions. Said compositions may be sterilized and/or contain adjuvants, 
such as preserving, stabilizing, wetting or emulsifying agents, solution 
promoters, salts for regulating the osmotic pressure, and/or buffers. In 
addition, they may also contain other therapeutically valuable substances. 
Said compositions are prepared according to conventional mixing, 
granulating, or coating methods, respectively, and contain about 0.1 to 
75%, preferably about 1 to 50%, of the active ingredient. 
The formulations may conveniently be presented in unit dosage form and may 
be prepared by any of the methods well-known in the art of pharmacy. All 
methods include the step of bringing the active ingredient into 
association with the carrier which constitutes one or more accessory 
ingredients. In general, the formulations are prepared by uniformly and 
intimately bringing the active ingredient into association with a liquid 
carrier or a finely divided solid carrier or both, and then, if necessary, 
shaping the product into the desired formulation. 
Finally, the present invention is a method of prophylactic or therapeutic 
treatment of cerebral ischemia, cerebral infarction, thromboembolic or 
hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, 
status epilepticus, schizophrenia, epilepsy, neurodegenerative disorders, 
Alzheimer's disease, Huntington's disease, or risk of cerebrovascular 
damage which comprises administering an antagonist effective amount for 
excitatory amino acid receptors of a compound of the formula I in unit 
dosage form. 
The invention is further elaborated by the representative examples as 
follows. Such examples are not meant to be limiting. 
EXAMPLES 
Preparation I 
.alpha.-[(Phenylcarbonyl)amino]-1,4-benzenediacetic acid 
##STR76## 
A solution of phenyl acetic acid (10.0 g, 73.5 mmol) in 25 ml 
methanesulfonic acid is treated with .alpha.-hydroxyhippuric acid (3.58 g, 
18.4 mmol) and the resulting solution stirred at room temperature for 24 
hours. The reaction mixture is poured onto ice (200 g) and the product 
extracted into ethyl acetate (3.times.200 ml). The combined organic layers 
are dried (Na.sub.2 SO.sub.4) and concentrated. The residue is 
recrystallized from THF/diisopropyl ether. A tan solid which is 
.alpha.-[(phenylcarbonyl)amino]-1,4-benzenediacetic acid is obtained (1.5 
g, 26%), mp 180.degree.-220.degree. C. 
Preparation 2 
Dimethyl .alpha.-[(phenylcarbonyl)amino]-1,4-benzenediacetate 
##STR77## 
A solution of .alpha.-[(phenylcarbonyl)amino]-1,4-benzenediacetic acid 
(1.31 g, 4.19 mmol) from the Preparation I above in 150 ml of THF is 
treated with a solution of diazomethane in ether until a persistent yellow 
color develops. The resulting solution is concentrated and the residue 
purified by silica gel chromatography (EtOAc). A waxy yellow solid of 
dimethyl .alpha.-[(phenylcarbonyl)amino]-1,4-benzenediacetate is obtained 
(1.30 g, 93%), mp 102-112 C..degree.. 
Anal. calcd for C.sub.19 H.sub.19 NO.sub.5 : 
C, 66.85; H, 5.61; N, 4.10. 
Found: C, 66.81; H, 5.71; N, 4.00. 
Example 1 
1,4-Benzenediacetic acid, .alpha.-amino-, (.+-.) 
##STR78## 
A solution of dimethyl .alpha.-[(phenylcarbonyl)amino]-1,4-benzenediacetate 
(1.00 g, 2.90 mmol) from the Preparation 2 above in 20 ml of 6N HCl is 
heated at reflux under N.sub.2 for 19 hours. The reaction mixture is 
cooled and extracted with a 1:1 toluene/ether solution (2.times.40 ml). 
The aqueous layer is concentrated and the residue dissolved in H.sub.2 O 
(10 ml) and freeze-dried. A solid, 1,4-benzenediacetic acid, a-amino-, 
(.+-.) is obtained (0.72 g, 76%), mp 205.degree. C. 
Anal. calcd. for C.sub.10 H.sub.11 NO.sub.4.2.2NH.sub.4 Cl: 
C, 37.05; H, 6.09; N, 13.61. 
Found: C, 37.00; H, 6.36; N, 13.58. 
Preparation 3 
4-Hydroxy-.alpha.-[(phenylcarbonyl)amino]-1,3-benzenediacetic acid 1-ethyl 
ester 
##STR79## 
A solution of 2-hydroxyphenylacetic acid (10.0 g, 66 mmol) and 
a-hydroxyhippuric acid (3.2 g, 16 mmol) in 50 ml formic acid is stirred at 
0.degree. C. for two hours. The solution is warmed to room temperature and 
allowed to stir for an additional 44 hours. The resulting solution is 
poured into 400 ml of ice water. The solid which formed is collected by 
suction filtration. The solid is dissolved in EtOH (150 ml) and sulfuric 
acid (5 ml) is added. The resulting solution is heated to reflux for 16 
hours. The reaction mixture is cooled and poured into H.sub.2 O (50 ml). 
The mixture is extracted into ethyl acetate, dried (Na.sub.2 SO.sub.4) and 
concentrated. The residue is purified by silica gel chromatography (80% 
EtOAc/Heptane). A white solid, 
4-hydroxy-.alpha.-[(phenylcarbonyl)amino]-1,3-benzenediacetic acid 1-ethyl 
ester is obtained (0.35 g, 5%). 
Example 2 
.alpha.-Amino-4-hydroxy-1,3-benzenediacetic acid 
##STR80## 
A solution of 4-hydroxy-.alpha.-[(phenylcarbonyl)amino]-1,3-benzenediacetic 
acid 1-ethyl ester from Preparation 3 above (0.50 g, 1.4 mmol) is 
dissolved in 15 ml of 3N HCl and the resulting solution heated at reflux 
for 24 hours. The reaction mixture is cooled to room temperature, 
filtered, and concentrated. The residue is dissolved in 1N HCl (25 ml) and 
extracted with 50% EtzO/toluene (2.times.25 ml). The aqueous layer is 
concentrated and dissolved in 10 ml H.sub.2 O. The solution is 
freeze-dried. An orange solid is obtained (0.25 g, 73%), mp 
180-210.degree. C., softens and foams. 
Anal.: Calcd for C.sub.10 H.sub.11 NO.sub.5 .multidot.0.40 C.sub.7 H.sub.6 
O.sub.2 .multidot. 
2.6 HCl .multidot.0.67 H.sub.2 O 
C, 39.89; H, 4.58; N, 3.69. 
Found: C, 39.89; H, 4.59; N, 3.69. 
Preparation 4 
Methyl .alpha.-(acetylamino)-3-hydroxybenzeneacetate 
##STR81## 
A solution of m-hydroxyphenylglycine (25.0 g, 0.15 mol) and NaOH (16 g) in 
40 ml H.sub.2 O is cooled to 0.degree. C. and acetic anhydride (12.5 g, 
0.22 mol) is added over a one-hour period. Additional NaOH (20 g) in 20 ml 
H.sub.2 O is added followed by acetic anhydride (12.5 g, 0.22 mol). The 
resulting solution is extracted with EtOAc (6.times.100 ml). The combined 
organic phases are dried (MgSO.sub.4) and concentrated. The residue (30 g) 
is dissolved in MeOH 200 ml and treated with a solution of diazomethane in 
ether until esterification was complete. The resulting solution is 
concentrated. A viscous oil of methyl 
.alpha.-(acetyl-amino)-3-hydroxybenzeneacetate is obtained (32.0 g). This 
material is used directly in the preparation of methyl 
.alpha.-(acetylamino)-3-(2-propenoxy)benzeneacetate hereinafter. 
Preparation 5 
Methyl .alpha.-(acetylamino)-3-(2-propenoxy)benzeneacetate 
##STR82## 
A suspension of the formula 9 from Preparation 4 (32.0 g, 0.143 mol), allyl 
bromide (17.6 g, 0.145 mol), and potassium carbonate (21.5 g, 0.156 mol) 
in 300 ml of acetone is heated at reflex for 24 hours. The reaction 
mixture is cooled, concentrated and the residue treated with EtOAc and 
H.sub.2 O. The organic phase is isolated, dried (MgSO.sub.4) and 
concentrated. The residue (32 g) is crystallized from hot heptane/ethyl 
acetate to afford pink needles of the formula 10 above (25.0 g, 66%), mp 
87.degree. C. 
Preparation 6 
Methyl .alpha.-(acetylamino)-3-hydroxy-2-(2-propenyl)-benzeneacetate and 
Methyl .alpha.-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate 
##STR83## 
A solution of methyl .alpha.-(acetylamino)-3-(2-propenoxy)benzeneacetate 
from Preparation 5 above (8.0 g, 32 mmol) in 15 g of p-dichlorobenzene is 
heated at 350.degree. C. for 16 hours in a sealed tube. The reaction 
mixture is cooled and the contents of the tube are purified by silica gel 
chromatography, eluting with CHCl.sub.3 to remove the p-dichlorobenzene 
and then with 5% MeOH-CHCl.sub.2 to remove the rearrangement products 
(methyl .alpha.-(acetylamino)-3-hydroxy-2-(2-propenyl) benzeneacetate, 
methyl .alpha.-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate). The 
rearrangement products (a 1:1 mixture of methyl 
.alpha.-(acetylamino)-3-hydroxy-2-(2-propenyl)-benzeneacetate, methyl 
.alpha.-(acetylamino)-3-hydroxy-4-(2propenyl)benzeneacetate) are separated 
by silica gel chromatography (Chromatotron/EtOAc). Recrystallization from 
diisopropylether/THF gives the compound of methyl 
.alpha.-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate above (2.60 
g, 33%) as a white solid, mp 143.degree.-145.degree. C. 
Preparation 7 
Methyl 
.alpha.-(acetylamino)-3-[(phenylcarbonyl)oxy]-4-(2propenyl)-benzeneacetate 
##STR84## 
A solution of methyl 
.alpha.-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate from 
Preparation 6 (1.5 g, 5.7 mmol) in CHCl.sub.3 (20 ml) and Et.sub.3 N (1 
ml) is treated with benzoyl chloride (1.0 g, 7.1 mmol). The resulting 
solution is stirred at room temperature for 4.5 hours. The reaction 
mixture is concentrated and the residue partitioned between EtOAc and 
saturated aqueous NaHCO.sub.3. The organic phases are combined, dried 
(MgSO.sub.4) and concentrated. The residue is purified by silica gel 
chromatography (50% EtOAc/Heptane). An oil of methyl 
.alpha.-(acetylamino)-3-[(phenylcarbonyl)oxy]-4-(2-propenyl)benzeneacetate 
is obtained (2.1 g, quantitative). 
Preparation 8 
.alpha.'-(Acetylamino)-3-[(phenylcarbonyl)oxy]-1,4-benzenediacetic acid 
4-methyl ester 
##STR85## 
A mixture of methyl 
.alpha.-(acetylamino)-3-[(phenylcarbonyl)oxy]-4-(2-propenyl)benzeneacetate 
from Preparation 7 above (0.6 g, 1.6 mmol), sodium metaperiodate (1.4 g, 
6.7 mmol) and RuCl.sub.3 .multidot.H.sub.2 O (10 mg, 0.05 mmol) in a 
H.sub.2 O (8 mL), CH.sub.3 CN (5 ml), CCl.sub.4 (5 ml) is stirred rapidly 
at 25.degree. C. for seven hours. The reaction mixture is poured into 50 
ml EtOAc and 50 ml (1N HCl). The organic phase is separated and the 
aqueous phase extracted with EtOAc (2.times.25 ml). The combined organic 
phases are washed with H.sub.2 O (25 ml, brine (25 ml) and NaHCO.sub.3 
(2.times.50 ml). The combined NaHCO.sub.3 washes are acidified with 1N HCl 
and extracted with EtOAc (3.times.70 ml). The combined organic phases are 
dried (MgSO.sub.4) and concentrated. The residue is dissolved in ether (20 
ml) and concentrated. A foamy white solid of 
.alpha.'-(acetylamino)-3-[(phenylcarbonyl)oxy]-1,4-benzenediacetic acid 
4-methyl ester above is obtained (0.39 g, 65%), mp 78-82.degree. C. (dec). 
Example 3 
1,4-Benzenediaoetic acid, .alpha.-amino-2-hydroxy-,-monohydrochloride, 
(.+-.) 
##STR86## 
A solution of 
.alpha.'-(acetylamino)-3-[(phenyl-carbonyl)oxy]-1,4-benzenediacetic acid 
4-methyl ester from Preparation 8 above (0.39 g, 1.04 mmol) in 60 ml of 6N 
HCl is heated at reflux for 24 hours. The reaction mixture is cooled and 
extracted with 1:1 toluene/ether (3.times.10 ml). The aqueous phase is 
decolorized with charcoal, filtered and concentrated. The residue is taken 
up in H.sub.2 O and freeze dried. A white solid of 1,4-benzenediacetic 
acid, .alpha.-amino-2-hydroxy-,monohydrochloride, (.+-.) is obtained 
(0.185 g, 64%), mp 125.degree. (softened). 
Anal. Calcd for C.sub.10 H.sub.11 NO.sub.5 .multidot.HCl.multidot.H.sub.2 O 
C, 42.70; H, 5.04; N, 4.98; Cl, 13.11. 
Found: C, 42.70: H, 4.55; N, 4.50; Cl, 13.11. 
Preparation 9 
Methyl 
4-(2-oxoethyl)-.alpha.-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]benz 
eneacetate 
##STR87## 
A solution of 
.alpha.'-(acetylamino)-3-[(phenylcarbonyl)oxy]-1,4-benzenediacetic acid 
4-methyl ester from Preparation 7 above in dichloromethane at -78.degree. 
C. is treated with ozone until starting material is consumed. The reaction 
mixture is purged with oxygen and warmed to 0.degree. C. The reaction 
mixture is treated with dimethyl sulfide (3 eq) and is warmed to room 
temperature. The reaction mixture is concentrated and the product, methyl 
4-(2-oxoethyl)-.alpha.-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]benz 
eneacetate, is isolated by silica gel chromatography. 
Preparation 10 
Methyl 
4-(cyanomethyl)-.alpha.-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]ben 
zeneacetate 
##STR88## 
A solution of methyl 
4-(2-oxoethyl)-.alpha.-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]benz 
eneacetate from Preparation 9 above in toluene containing pyridine (2.3 eq) 
is treated with O,N-bistrifluoroacetyl hydroxyl amine (1.0 eq). The 
resulting solution is allowed to stir until no starting material remains. 
The reaction mixture is washed with saturated eq NaHCO.sub.3 solution, 
dried (MgSO.sub.4), and concentrated. The product of the formula 15 above 
is purified by silica gel chromatography. 
Preparation 11 
Methyl 
.alpha.-(phenylcarbonyl)amino]-3-[(phenylcarbonyl)-oxy]-4-[[2-(tributylsta 
nnyl)-1H-tetrazol-5-yl]methyl]-benzeneacetate 
##STR89## 
A solution of methyl 
4-(cyanomethyl)-.alpha.-[(phenylcarbonyl)amino]3-[(phenylcarbonyl)oxy]benz 
eneacetate from Preparation 10 above in dioxane is treated with 
tri-n-butyltinazide (2.5 eq). The resulting solution is heated at 
120.degree. C. until no starting material remains. The reaction mixture is 
concentrated and the product of methyl 
.alpha.-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]-4-[[2-(tributylsta 
nnyl)-1H-tetrazol-5-yl]methyl]benzeneacetate is purified by silica gel 
chromatography. 
Example 4 
.alpha.-Amino-3-hydroxy-4-(1H-tetrazol-5-ylmethyl)benzeneacetic acid 
##STR90## 
A solution of methyl 
.alpha.-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)-oxy]-4-[[2-(tributylst 
annyl)-1H-tetrazol-5-yl]methyl]benzeneacetate from the Preparation 11 above 
in 6N HCl is heated at reflux until consumed. The reaction mixture is 
cooled to room temperature and extracted with 1:1 ether/toluene. The 
aqueous phase is concentrated to give the product of 
.alpha.-amino-3-hydroxy-4-(1H-tetrazol-5-ylmethyl)-benzeneacetic acid. 
Preparation 12 
Methyl 3-hydroxy-4-methylbenzoate 
##STR91## 
A solution of 3-hydroxy-4-methylbenzoic acid (26.1 g, 0.17 mol) in 200 mL 
of diethylether is treated with a solution of diazomethane in ether until 
a persistent yellow color develops. The resulting solution is stirred for 
24 hours. The resulting solution is concentrated and the residue is 
crystallized from CH.sub.2 Cl.sub.2. A white solid which is methyl 
3-hydroxy-4-methylbenzoate is obtained (26.5 g, 93%). 
Preparation 13 
Methyl 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-methylbenzoate 
##STR92## 
A solution of 3-hydroxy-4-methylbenzoate (5.55 g, 33 mmol) from Preparation 
12, tert-butyldimethylsilyl chloride (7.6 g, 50 mmol), and triethylamine 
(14 mL, 100 mmol) in 50 mL CH.sub.2 Cl.sub.2 is stirred at room 
temperature for 24 hours. An additional 25 mL of CH.sub.2 Cl.sub.2 is 
added and washed with water. The organic layer is dried (MgSO.sub.4) and 
concentrated. The product is isolated by silica gel chromatography (100% 
CH.sub.2 Cl.sub.2). An oil of methyl 3- 
[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-methylbenzoate is obtained 
(9.05 g, 97%). 
Preparation 14 
Methyl 4-(bromomethyl)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]benzoate 
##STR93## 
A solution of methyl 
3-[(1,1-dimethylethyl)dimethylsilyl]oxy-4-methylbenzoate (11.36 g, 40.5 
mmol) from Preparation 13, N-bromosuccinimide (6.5 g, 36.5 mmol), and AIBN 
100 mg, 0.61 mmol) in CCl.sub.4. The reaction mixture is stirred at room 
temperature for 1 hour while exposed to a high intensity light bulb. The 
precipitate is removed by suction filtration and the filtrate is 
concentrated. The residue is purified by silica gel chromatography (1% 
tetrahydrofuran/petroleum ether). An oil of methyl 
4-(bromomethyl)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]benzoate is 
obtained 99.87 g, 75%). 
Preparation 15 
4-(Bromomethyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanol 
##STR94## 
A solution of methyl 
4-(bromomethyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzoate (1.59 g, 
4.2 mmol) from Preparation 14 in THF 15 mL), cooled to -78.degree. C. is 
treated with diisobutylaluminum hydride (1M, 10.4 mL, 10.4 mmol). The 
reaction mixture is stirred for 3.5 hours. The reaction mixture is treated 
with 20 mL of a saturated potassium-, sodium-tartrate solution, 
diethylether (200 mL) and is allowed to warm to room temperature. The 
organic phase is separated, dried (MgSO.sub.4), and concentrated. The 
residue is purified by silica gel chromatography (1% MeOH/CH.sub.2 
Cl.sub.2). An oil of 
4-(bromomethyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanol 
is obtained (1.02 g, 74%). 
Preparation 16 
2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[(1,1-dimethylethyl) 
dimethylsilyl]oxy]methyl]-N,N,N-triethylbenzenemethanaminium bromide 
##STR95## 
A mixture of 
4-(bromomethyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanol 
(6.35 g, 19.2 mmol) from Preparation 15, tert-butyldimethylsilyl chloride 
(4.3 g, 28.8 mmol), triethylamine (5.3 mL, 38.3 mmol), and 
dimethylaminopyridine (90 mg) in dichloromethane (50 mL) is stirred at 
room temperature for 24 hours. Dichloromethane (1 L) is added and the 
organic phase washed with H.sub.2 O 100 mL). The organic phase is dried 
(MgSO.sub.4) and concentrated. The residue is purified by silica gel 
chromatography (2.5% MeOH/CH.sub.2 Cl.sub.2 followed by 5% 
MeOH/CHCl.sub.2). A yellow-orange solid of 
2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-4-[[[(1,1-dimethylethyl) 
dimethylsilyl]oxy]-methyl]-N,N,N-triethylbenzenemethanaminium bromide is 
obtained (7.68 g, 73%). 
Anal. Calc. for C.sub.26 H.sub.52 NO.sub.2 Si.sub.2 Br 
C, 57.11; H, 9.59; N, 2.56; Br, 14.61. 
Found: C, 57.11; H, 9.50; N, 2.44; Br, 14.32. 
Preparation 17 
Diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[(1,1-dimethylethyl) dimet 
hylsilyl]oxy]methyl]-phenyl]methyl]phosphonate 
##STR96## 
A mixture of 
2-[[(1,1-dimethylethyl)dimethylsilyl]xoy]-4-[[[(1,1-dimethylethyl) 
dimethylsilyl]oxy]-methyl]-N,N,N-triethylbenzenemethanaminium bromide 
(2.25 g, 4.12 mmol) from Preparation 16 and triethylphosphite (1.4 mL, 
8.23 mmol) is heated under an aspirator vacuum to 144.degree. C. for 3.5 
hours. The residue is purified by silica gel chromatography (2.5% 
MeOH/CH.sub.2 Cl.sub.2 followed by 5% MeOH/CH.sub.2 Cl.sub.2). A colorless 
oil of diethyl [[2-[[(1,1-dimethylethyl) 
dimethylsilyl]oxy]-4-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]phenyl 
]methyl]phosphonate is obtained 1.51 g, 73%). 
Preparation 18 
Diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(hydroxymethyl)phenyl]methyl 
]phosphonate 
##STR97## 
A solution of diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[(1,1-dimethylethyl)dimeth 
ylsilyl]oxy]methyl]phenyl]methyl]phosphonate (3.23 g, 6.4 mmol) from 
Preparation 17 in ethanol (30 mL) at 0.degree. C. is treated with 1 mL of 
1N HCl. The mixture is stirred at 0.degree. C. for 2 hours. The solution 
is poured onto 500 mL EtOAc and water (50 mL). The organic phase is 
separated, dried (MgSO.sub.4), and concentrated. The residue is purified 
by silica gel chromatography (2.5% MeOH/CH.sub.2 Cl.sub.2 followed by 5% 
MeOH/CH.sub.2 Cl.sub.2). A colorless oil of diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(hydroxymethyl)phenyl]methyl 
]phosphonate is obtained (1.73 g, 69%). 
Preparation 19 
Diethyl 
[[2[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-formylphenyl]methyl]phosphona 
te 
##STR98## 
A solution of oxalylchloride (0.6 g, 6.7 mmol) in 20 mL methylene chloride 
is cooled to -70.degree. C. Dimethylsulfoxide (0.6 mL, 8.4 mmol) is added 
dropwise. The solution is warmed to -30.degree. C. then cooled to 
-70.degree. C. A solution of diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(hydroxymethyl)phenyl]methyl 
]phosphonate (1.73 g, 4.45 mmol) from Preparation 18 in methylenechloride 
(15 mL) is added to the reaction mixture. The reaction mixture is stirred 
for 0.5 hours then warmed to -35.degree. C. Triethylamine (4.7 mL, 33.5 
mmol) is added and the mixture allowed to warm to room temperature. 
Methylenechloride (400 mL) is added and the organic phase is washed with 
100 mL H.sub.2 O. The organic phase is dried (MgSO.sub.4) and 
concentrated. The residue is passed through a 200-g silica gel plug using 
5% MeOH/CH.sub.2 Cl.sub.2 as the eluent. An oil of diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-formylphenyl]methyl]phosphon 
ate is obtained (1.67 g, 97%). 
Preparation 20 
Diethyl 
[[4-(aminocyanomethyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]met 
hyl]phosphonate 
##STR99## 
A solution of diethyl 
[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy-4-formylphenyl]methyl]phosphona 
te (1.67 g, 4.32 mmol) from Preparation 19 in CH.sub.2 Cl.sub.2 (5 mL) is 
treated with trimethylsilylcyanamide (0.72 mL, 5.4 mmol) and ZnI.sub.2 (10 
mg). The reaction mixture is stirred at room temperature for 30 minutes. A 
solution of methanol (20 mL) saturated with ammonia gas is added. The 
mixture is heated to 45.degree. C. for 3 hours. The reaction mixture is 
concentrated. The residue is taken up in diethylether and H.sub.2 O. The 
organics were separated, dried (MgSO.sub.4), and concentrated. The residue 
is purified by silica gel chromatography (1% MeOH/CH.sub.2 Cl.sub.2 
followed by 2.5% MeOH/CH.sub.2 Cl.sub.2 followed by 5% MeOH/CH.sub.2 
Cl.sub.2). An oil of diethyl 
[[4-(aminocyanomethyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]met 
hyl]phosphonate is obtained (600 mg, 34%). 
Example 5 
(.+-.)-1.alpha.-amino-3-hydroxy-4-(phosphonomethyl)-benzeneacetic acid 
monohydrochloride 
##STR100## 
A solution of diethyl [[4-(aminocyanomethyl)-2-[[1,1-dimethylethyl) 
dimethylsilyl]oxy]phenyl]methyl]-phosphonate from Preparation 20 (600 mg, 
1.54 mmol) in 5 mL of 6N HCl is heated to 95.degree. C. for 16 hours. The 
aqueous phase is concentrated to dryness and the residue is triturated 
with acetone. The solid was collected by suction filtration and washed 
with acetone. The solid is dried under vacuum at 100.degree. C. A white 
solid of (.+-.)-1.alpha.-amino-3-hydroxy-4-(phosphonomethyl)-benzeneacetic 
acid monohydrochloride is obtained (350 mg, 81%). 
Anal. Calc. for C.sup.9 H.sup.12 NO.sup.6 P.multidot.HCl.multidot.NH.sub.4 
Cl.multidot.1.44C.sub.3 H.sub.6 O 
C, 36.80; H, 5.94; N, 6.44; Cl, 16.31. 
Found: C, 36.95; H, 5.63; N, 6.69; Cl, 15.08.