Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-15
2003-08-12
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S219000, C546S236000
Reexamination Certificate
active
06605723
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of the compounds of the formulae
where R
1
-R
4
are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R
5
-R
8
are, independently from each other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts, especially the compounds formula I-a. These compounds are active as NMDA (N-methyl-D-aspartate) receptor-subtype selective blockers.
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmacological properties. Possible therapeutic indications for NMDA receptor subtype specific blockers such as the compounds of formula I include acute forms of neurodegeneration caused, e.g., by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, diseases such as schizophrenia, anxiety and depression and acute/chronic pain. Ethanesulfonyl-piperidine derivatives that are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers also have a key function in modulating neuronal activity and plasticity and are key players in mediating processes underlying development of CNS including learning and memory formation and function.
The compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, e.g. in WO 95/25721, for example by processes described below, which comprises
a) reacting a compound of formula
with a compound of formula
to a compound of formula
wherein the substituents are as defined above and X signifies a leaving group, and, if desired,
b) converting the compound of formula I obtained into a pharmaceutically acceptable acid addition salt, and, if desired,
c) converting a racemic mixture at the stage of formula III or at the stage of formula I into enantiomeric compounds III-a, III-b
or I-a, I-b respectively, thus obtaining optically pure compounds. However, the above processes usually lead to yields of 10% or less of the desired compound due to the poor efficiency of the methods employed, i.e. resolution by crystallization of diasteromeric salts.
SUMMARY OF THE INVENTION
It has now been found that the compounds of formula I-a and I-b can be prepared more effectively and with considerably higher yield if manufactured according to reaction scheme 1.
All starting materials are known compounds or may be prepared by methods known in the art.
wherein
R
1
-R
8
are as defined above;
R
9
is an amino protecting group, preferably benzyl;
R
10
and R
10′
are independently a carboxylic acid protecting group;
Y and X represent independently a leaving group; and
AZ signifies a mineral acid from the group of HBF
4
, H
2
SO
4
, HPF
6
, HBr, HI, HCl, HSbF
6
or HClO
4
, or a strong organic acid from the group of C
1-8
-alkylSO
3
H, picric acid, formic acid, a lower alkylcarboxylic acid such as e.g. acetic acid, propionic acid or trifluoroacetic acid, or a dicarboxylic acid, such as e.g. oxalic acid, succinic acid, maleic acid, tartaric acid or phthalic acid.
Step 5 (asymmetric hydrogenation) and step 6 (deprotection of the ring nitrogen) can be inverted (Step 6* and step 5*).
Accordingly, this invention is directed to a process (Process A) for the preparation of compounds of formulae
wherein R
1
-R
4
are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R
5
-R
8
are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts; which process comprises
a) reacting a protected amino acid ester (1)
with a 4-substituted butyric acid derivative (2)
wherein R
9
is an amino protecting group, preferably benzyl; R
10
and R
10′
are independently a carboxylic acid protecting group; and Y represents a leaving group; in the presence of a base to obtain the protected alkoxycarbonylmethyl amino butyric acid derivative (3);
b) cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3)
wherein the symbols are as defined above to obtain the protected alkyl 3-oxo-piperidine carboxylate salt(4);
c) benzylating the protected alkyl 3-oxo-piperidine carboxylate salt (4)
wherein AZ signifies a mineral acid or a strong organic acid to obtain the benzylated protected alkyl 3-oxo-piperidine carboxylate (5);
d) decarboxylating the benzylated protected alkyl 3-oxo-piperidine carboxylate (5)
wherein the symbols are as defined above; in presence of a strong acid to obtain the salt of formula (6);
e) asymmetrically hydrogenating the salt of formula (6)
wherein R
9
is an amino protecting group; in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and an organic or inorganic base, to obtain the compound of formula (7a) or (7b); and deprotecting the compound of formula (7a) or (7b)
wherein the symbols are as defined above; or
asymmetrically hydrogenating the salt of formula (6bis)
in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and a organic or an inorganic base, to obtain the piperidine derivative of formula III-a or III-b; and
f) reacting the piperidine derivative of formula III-a or III-b
wherein the symbols are as defined above; with the reactive vinyl sulfone intermediate
which is obtained by treating the sulfone derivative of formula II
wherein R
1
-R
4
are as defined above; and X is a leaving group; with a base; in the presence of a base to form the desired compound of formula I-a or I-b.
The above process provides compounds of formulae I-a and I-b, which are the cis compounds of the compound of formula I. By this process, trans compounds of formula I are excluded.
The above process is particularly preferred for the preparation of compounds of formula I-a. In this preferred process, the ruthenium complex of step e), the diphosphine has an (S) configuration and the diamine has an (R,R) configuration.
This invention is also directed to Process B, which is the above process for the preparation of compounds of formulae
wherein R
1
-R
4
are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R
5
-R
8
are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts; which process comprises
a) deprotonating a substituted thiophenol derivative of formula (8)
wherein the symbols are as defined above; in presence of a strong inorganic or organic base and subsequently reacting it with 2-haloethanol to obtain the thioether of formula (9);
b) oxidizing the thioether of formula (9)
wherein the symbols are as defined above; in presence of an oxidative agent to obtain the sulfone derivative of formula (10);
c) replacing the hydroxy group of the sulfone derivative of formula (10)
wherein the symbols are as defined above; by a halogen atom in the presence of pyridine in dichloromethane to obtain the sulfon
Crameri Yvo
Scalone Michelangelo
Waldmeier Pius
Widmer Ulrich
Covington Raymond
Hoffman-La Roche Inc.
Johnston George W.
Prior Kimberly J.
Rocha-Tramaloni Patricia S.
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