Title: Heterocyclic sulfonamide inhibitors of beta amyloid production
Abstract: Compounds of Formula (I), ##STR1##wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, T, W, X, Y and Z are as defined herein are provided, together with pharmaceutically acceptable salt, hydrates and/or prodrugs thereof. Methods of using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's Disease and Down's syndrome are described
Patent Number: 6,878,742 Issued on 04/12/2005 to Kreft, et al.
| Inventors:
|
Kreft; Anthony F. (Langhorne, PA);
Cole; Derek C. (New City, NY);
Woller; Kevin R. (Ayer, MA);
Stock; Joseph R. (Monroe, NY);
Diamantidis; George (Randolph, NJ);
Kubrak; Dennis M. (Philadelphia, PA);
Kutterer; Kristina M. (Westwood, NJ);
Moore; William J. (Marlborough, MA);
Casebier; David S. (Carlisle, MA)
|
| Assignee:
|
Wyeth (Madison, NJ);
ArQule, Inc. (Woburn, MA)
|
| Appl. No.:
|
455674 |
| Filed:
|
June 5, 2003 |
| Current U.S. Class: |
514/445; 514/473; 549/65; 549/479 |
| Intern'l Class: |
A61K 031//38; A61K 031//34; C07D 333//32; C07D 307//02 |
| Field of Search: |
514/445,473
549/65,479
|
References Cited [Referenced By]
U.S. Patent Documents
| 5464853 | Nov., 1995 | Chan et al.
| |
| 5514691 | May., 1996 | Chan et al.
| |
| 5571821 | Nov., 1996 | Chan et al.
| |
| 5591761 | Jan., 1997 | Chan et al.
| |
| 5593846 | Jan., 1997 | Schenk.
| |
| 5594021 | Jan., 1997 | Chan et al.
| |
| 5624937 | Apr., 1997 | Reel.
| |
| 5703129 | Dec., 1997 | Felsenstein.
| |
| 5852007 | Dec., 1998 | Chatterjee.
| |
| 5981168 | Nov., 1999 | Reiner.
| |
| 6248775 | Jun., 2001 | Vazquez.
| |
| 6376523 | Apr., 2002 | Chan et al.
| |
| 6566536 | May., 2003 | Muller et al.
| |
| 6610734 | Aug., 2003 | Kreft et al.
| |
| 2002/0183361 | Dec., 2002 | Kreft et al.
| |
| 2003/0013892 | Jan., 2003 | Resnick et al.
| |
| Foreign Patent Documents |
| 510700 | Oct., 1992 | EP.
| |
| 652009 | May., 1995 | EP.
| |
| 1088821 | Apr., 2001 | EP.
| |
| 1172361 | Jan., 2002 | EP.
| |
| 5-148233 | Jun., 1993 | JP.
| |
| 11-343279 | Dec., 1999 | JP.
| |
| WO95/29904 | Nov., 1995 | WO.
| |
| WO98/03166 | Jan., 1998 | WO.
| |
| WO98/22104 | May., 1998 | WO.
| |
| WO98/22493 | May., 1998 | WO.
| |
| WO00/09107 | Feb., 2000 | WO.
| |
| WO00/50391 | Aug., 2000 | WO.
| |
| WO01/23379 | Apr., 2001 | WO.
| |
| WO01/27091 | Apr., 2001 | WO.
| |
| WO01/27108 | Apr., 2001 | WO.
| |
| WO-03/050062 | Jun., 2003 | WO.
| |
| WO-03/050063 | Jun., 2003 | WO.
| |
| WO-03/103660 | Dec., 2003 | WO.
| |
Other References
A. Larner et al, "Review--Central & Peripheral Nervous Systems--Alzheimer's
Disease: Towards Therapeutic Manipulation of the Amyloid Precursor Protein
and Amyloid .beta.-peptides", Exp. Opin. Ther. Patents, 7(10):1115-1127
(1997).
C. Moore et al, "Inhibition of .beta.-amyloid Formation as a Therapeutic
Strategy", Exp. Opin. Ther. Patents, 9(2):135-146 (1999).
V. John et al, "Alzheimer's Disease: Recent Advances on the Amyloid
Hypothesis", in Annual Reports in Medicinal Chemistry, Chapter 2, pp.
11-20 (1997).
G. Rishton et al, "Fenchylamine Sulfonamide Inhibitors of Amyloid .beta.
Peptide Production by the .gamma.-Secretase Proteolytic Pathway: Potential
Small-Molecule Therapeutic Agents for the Treatment of Alzheimer's
Disease", J. Med. Chem., 43(12):2297-2299 (Jun. 15, 2000).
B. Testa et al, "Prodrugs Revisited: The "Ad Hoc" Approach as a Complement
to Ligand Design", Medicinal Research Reviews, 16(3):233-241 (May, 1996).
D. Skovronsky et al, ".beta.-Secretase Revealed: Starting Gate for Race to
Novel Therapies for Alzheimer's Disease", TIPS, 21:161-163 (May, 2000).
A. Ghosh et al, "Design of Potent Inhibitors for Human Brain Memapsin 2
(.beta.-Secretase)", J. Am. Chem. Soc., 122:3522-3523 (2000).
W. Esler et al, "Transition-State Analogue Inhibitors of .gamma.-Secretase
Bind Directly to Presenilin-1", Nature Cell Biology, 2:428-434 (Jul.,
2000).
Y-M. Li et al, "Photoactivated .gamma.-Secretase Inhibitors Directed to the
Active Site Covalently Label Presenilin 1", Nature, 405:689-694 (Jun.,
2000).
M. Wolfe et al, "A Substrate-Based Difluoro Ketone Selectively Inhibits
Alzheimer's .gamma.-Secretase Activity", J. Med. Chem., 41:6-9 (Jan. 1,
1998).
S. Sinha et al, "Purification and Cloning of Amyloid Precursor Protein
.beta.-Secretase from Human Brain", Nature, 402:537-540 (Dec., 1999).
A. Goate, "Monogenetic Determinants of Alzheimer's Disease: APP Mutations",
CMLS Cell. Mol. Life Sci., 54:897-901 (Sep., 1998).
M. Sabbagh et al, ".beta.-Amyloid and Treatment Opportunities for
Alzheimer's Disease", Alzheimer's Disease Review, 3:1-19 (1997).
C. Augelli-Szafran et al, .beta.-Amyloid as a Target for Alzheimer's
Disease Therapy, in Annual Reports in Medicinal Chemistry, Chapter 3, pp.
21-30 (1999).
J-C. Dodart et al, "The .beta.-Amyloid Precursor Protein and its
Derivatives: from Biology to Learning and Memory Processes", Reviews in
the Neurosciences, 11(2-3):75-93 (2000).
D. Small et al, "Alzheimer's Disease and the Amyloid .beta. Protein: What
is the Role of Amyloid?", Journal of Neurochemistry, 73(2):443-449 (Aug.,
1999).
J. Naslund et al, "Correlation Between Elevated Levels of Amyloid
.beta.-Peptide in the Brain and Cognitive Decline", JAMA,
283(12):1571-1577 (Mar., 2000).
Q-X. Li et al, "The Amyloid Precursor Protein of Alzheimer Disease in Human
Brain and Blood", Journal of Leukocyte Biology, 66:567-574 (Oct., 1999).
S. Wagner et al, "Modulation of Amyloid .beta. Protein Precursor Processing
as a Means of Retarding Progression of Alzheimer's Disease", The Journal
of Clinical Investigation, 104(10):1329-1332 (Nov., 1999).
Y. Han et al, "Total Asymmetric Synthesis of Highly Constrained Amino Acids
Isopropyl-2', 6'-Dimethyl-Tyrosines", Tetrahedron Letters,
38(29):5135-5138 (1997).
M. Findeis et al, "Modified-Peptide Inhibitors of Amyloid .beta.-Peptide
Polymerization", Biochemistry, 38(21):6791-6800 (May, 1999).
Wermuth et al., "Molecular variations based on isosteric replacements",
Prac. Med. Chem., Academic Press, pp. 203-237 (Feb. 1996).
|
Primary Examiner: Lambkin; Deborah C.
Attorney, Agent or Firm: Howson and Howson
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No.
10/014,304, filed Dec. 11, 2001, now U.S. Pat. No. 6,610,734 which claims
the benefit of the priority of U.S. Provisional Patent Application No.
60/255,105, filed Dec. 13, 2000, now abandoned.
Claims
What is claimed is:
1. A compound of Formula (I), or pharmaceutically acceptable salt thereof,
wherein Formula (I) has the structure:
##STR78##
wherein:
R.sub.1, R.sub.2, R.sub.3, and R.sub.5 are independently hydrogen or
CH.sub.3 ;
R.sub.4 is selected from the group consisting of alkyl, substituted alkyl,
alkylcycloalkyl, substituted alkylcycloalkyl, alkylOH, substituted
alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted
alkylpyridyl, piperdinyl, substituted piperidinyl, tetrahydrothiopyran,
substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl,
substituted phenyl, benzyl, substituted benzyl and alkylNHR.sub.7 ;
R.sub.7 is alkyl;
or R.sub.3 and R.sub.4 may be joined to form a monocyclic ring structure;
R.sub.6 is selected from the group consisting of hydrogen and halogen;
T is
##STR79##
W, Y and Z are independently selected from the group consisting of C and
CR.sub.10 ;
R.sub.10 is selected from the group consisting of hydrogen and halogen,
with the proviso that at least one of W, Y and Z must be C;
X is selected from the group consisting of O, S, and SO.sub.2 ;
provided that when the compound contains one or more chiral centers, at
least the .alpha.-amino alcohol chiral center must be of
S-stereochemistry.
2. The compound according to claim 1, wherein:
R.sub.1, R.sub.2, R.sub.3, and R.sub.5 are hydrogen;
R.sub.4 is selected from the group consisting of alkyl and substituted
alkyl;
X is selected from the group consisting of O and S.
3. The compound according to claim 1, wherein:
R.sub.1, R.sub.2, and R.sub.5 are H;
R.sub.3 and R.sub.4 are joined to form the monocyclic ring structure;
X is selected from the group consisting of O and S.
4. The compound according to claim 1, wherein:
R.sub.1, R.sub.2, R.sub.3, and R.sub.5 are hydrogen;
R.sub.4 is selected from the group consisting of butyl, substituted butyl,
propyl, pentyl, and substituted pentyl.
5. The compound according to claim 1, wherein:
R.sub.1 and R.sub.2 are CH.sub.3 ;
R.sub.3 and R.sub.5 are hydrogen;
R.sub.4 is selected from the group consisting of butyl, substituted butyl,
pentyl, and substituted pentyl;
W, Y and Z are independently selected from the group consisting of C and
CR.sub.10 ;
with the proviso that at least one of W, Y, and Z must be C.
6. A prodrug or hydrate of a compound of Formula (I), or pharmaceutically
acceptable salt thereof, wherein Formula (I) has the structure:
##STR80##
wherein:
T is
##STR81##
R.sub.1, R.sub.2, and R.sub.5 are hydrogen;
R.sub.4 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkylOH, substituted alkylOH,
alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl,
piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted
tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted
phenyl, benzyl, substituted benzyl, and alkylNHR.sub.7 ;
R.sub.7 is alkyl;
R.sub.3 is H or R.sub.3 and R.sub.4 may be joined to form a monocyclic ring
structure;
R.sub.6 is selected from the group consisting of hydrogen and halogen;
W, Y and Z are independently selected from the group consisting of C and
CR.sub.10 ;
R.sub.10 is selected from the group consisting of hydrogen and halogen,
with the proviso that at least one of W, Y and Z must be C;
X is selected from the group consisting of O, S, and SO.sub.2 ;
provided that when the compound contains one or more chiral centers, at
least the .alpha.-amino alcohol chiral center must be of
S-stereochemistry.
7. The prodrug according to claim 6, wherein the prodrug is an ester or
carbamate thereof.
Description
BACKGROUND OF THE INVENTION
This invention relates to inhibitors of beta amyloid production, which have
utility in the treatment of Alzheimer's disease.
Alzheimer's Disease (AD) is the most common form of dementia (loss of
memory) in the elderly. The main pathological lesions of AD found in the
brain consist of extracellular deposits of beta amyloid protein in the
form of plaques and angiopathy and intracellular neurofibrillary tangles
of aggregated hyperphosphorylated tau protein. Recent evidence has
revealed that elevated beta amyloid levels in brain not only precede tau
pathology but also correlate with cognitive decline. Further suggesting a
causative role for beta amyloid in AD, recent studies have shown that
aggregated beta amyloid is toxic to neurons in cell culture.
Beta amyloid protein is composed mainly of 39-42 amino acid peptides and is
produced from a larger precursor protein called amyloid precursor protein
(APP) by the sequential action of the proteases beta and gamma secretase.
Although rare, cases of early onset AD have been attributed to genetic
mutations in APP that lead to an overproduction of either total beta
amyloid protein or its more aggregation-prone 42 amino acid isoform.
Furthermore, people with Down's Syndrome possess an extra chromosome that
contains the gene that encodes APP and thus have elevated beta amyloid
levels and invariably develop AD later in life.
There continues to be an unmet need for compositions useful in inhibiting
beta amyloid production and in the treatment of the effects of Alzheimer's
Disease (AD).
SUMMARY OF THE INVENTION
The present invention provides heterocyclic sulfonamide derivatives of
2-amino-1-alcohols and related homologs that have been found to
specifically inhibit the production of beta amyloid protein from APP and
to be capable of passing through the blood-brain barrier. These compounds
are useful for the treatment of conditions in which beta amyloid levels
are elevated (e.g., AD, Down's Syndrome). Systemic administration of these
compounds to subjects at risk of, or suffering from, these diseases lowers
beta amyloid protein levels with subsequent reduction in the toxic beta
amyloid aggregates in the brains of these patients.
In one aspect, the present invention provides a compound of Formula (I), as
defined herein, pharmaceutically acceptable salts, hydrates, or prodrugs
thereof In one embodiment, the compounds of Formula (I) are
thiophenesulfonamides. In another embodiment, the compounds of Formula (I)
are furansulfonamides. Among the particularly desirable compounds are
those having a halogen in the 5-position of the heterocycle (e.g., 5-halo
thiophenesulfonamides) and .beta.-branches in the side chain of the
primary alcohol.
In another aspect, the invention provides a pharmaceutical composition
containing one or more compounds of Formula (I) and a physiologically
compatible carrier.
In yet another aspect, the invention provides a method of inhibiting beta
amyloid production in a subject by delivering a compound of Formula (I).
In still another aspect, the invention provides a method of treating
Alzheimer's Disease (AD) in a subject by administering a compound of
Formula (I) to the subject in an amount sufficient to alleviate the
symptoms or progress of AD.
These and other aspects of the invention will be apparent to one of skill
in the art upon reading of the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention consists of compounds of Formula (I), their pharmaceutical
formulations, and their use in modulating beta amyloid production in
subjects at risk for, or suffering from, AD or other diseases resulting
from elevated levels of beta amyloid protein in the brain. The compounds
of Formula (I) include pharmaceutically acceptable salts and/or hydrates
or prodrugs thereof, wherein:
##STR2##
R.sub.1 and R.sub.2 are independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, CF.sub.3, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
phenyl, substituted phenyl, and (CH.sub.2).sub.n (1,3)dioxane, where n is
2 to 5;
R.sub.3 is selected from the group consisting of hydrogen, alkyl, and
substituted alkyl;
R.sub.4 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl,
phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn,
substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl,
alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl, CH(OH)substituted
phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,
N-substituted-piperidinyl, piperidinyl, substituted piperidinyl,
tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane,
substituted 2-indane, phenyl, substituted phenyl, alkylNHR.sub.7, and
substituted alkylNHR.sub.7 ;
with the proviso that R.sub.3 and R.sub.4 are not both hydrogen;
R.sub.7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
benzyl, substituted benzyl, alkylOH, substituted alkylOH, alkylSR.sub.8,
or substituted alkylSR.sub.8 ;
R.sub.8 is alkyl, substituted alkyl, benzyl, or substituted benzyl;
or R.sub.3 and R.sub.4 may be joined to form a ring;
R.sub.5 is selected from the group consisting of hydrogen, lower alkyl,
substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, CH.sub.2 cycloalkyl, substituted CH.sub.2 cycloalkyl,
benzyl, substituted benzyl, and CH.sub.2 CH.sub.2 QR.sub.9 ;
Q is O, NH or S;
R.sub.9 is lower alkyl, substituted lower alkyl, phenyl, or substituted
phenyl;
R.sub.6 is selected from the group consisting of hydrogen, halogen and
CF.sub.3 ;
T is selected from the group consisting of
##STR3##
W, Y and Z are independently selected from the group consisting of C,
CR.sub.10 and N;
R.sub.10 is selected from the group consisting of hydrogen and halogen,
with the proviso that at least one of W, Y and Z must be C;
X is selected from the group consisting of O, S, SO.sub.2, and NR.sub.11 ;
R.sub.11 is selected from the group consisting of hydrogen, lower alkyl,
substituted lower alkyl, benzyl, substituted benzyl, phenyl, and
substituted phenyl;
provided that when the compound contains one or more chiral centers, at
least one of the chiral centers must be of S-stereochemistry.
The point of attachment of the W--X--Y-Z-C heterocyclic ring to the
SO.sub.2 group is not a limitation of the present invention. However, in
one preferred embodiment, the ring is attached to the SO.sub.2 group
through a carbon-atom. However, the ring may be attached through O, S, or
N heteroatoms.
The compounds of the invention may contain one or more asymmetric carbon
atoms and some of the compounds may contain one or more asymmetric
(chiral) centers and may thus give rise to optical isomers and
diastereomers. While shown without respect to stereochemistry in Formula
(I), when the compounds of Formula (I) contain one or more chiral centers,
at least one of the chiral centers is of S-stereochemistry. Most
preferably, the carbon atom to which N, T, R.sub.3 and R.sub.4 are
attached is of S-stereochemistry. Thus, the invention includes such
optical isomers and disastereomers; as well as the racemic and resolved,
enantiomerically pure stereoisomers; as well as other mixtures of the R
and S stereoisomers, and pharmaceutically acceptable salts, hydrates, and
prodrugs thereof.
The term "alkyl" is used herein to refer to both straight- and
branched-chain saturated aliphatic hydrocarbon groups having one to ten
carbon atoms, preferably one to eight carbon atoms and, most preferably,
one to six carbon atoms; as used herein, the term "lower alkyl" refers to
straight- and branched-chain saturated aliphatic hydrocarbon groups having
one to six carbon atoms; "alkenyl" is intended to include both straight-
and branched-chain alkyl group with at least one carbon-carbon double bond
and two to eight carbon atoms, preferably two to six carbon atoms;
"alkynyl" group is intended to cover both straight- and branched-chain
alkyl groups with at least one carbon-carbon triple bond and two to eight
carbon atoms, preferably two to six carbon atoms.
The terms "substituted alkyl", "substituted alkenyl", and "substituted
alkynyl" refer to alkyl, alkenyl, and alkynyl as just described having
from one to three substituents selected from the group including halogen,
CN, OH, NO.sub.2, amino, aryl, heterocyclic, substituted aryl, substituted
heterocyclic, alkoxy, substituted alkoxy, aryloxy, substituted alkyloxy,
alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may
be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided
that the attachment constitutes a stable chemical moiety.
The term "aryl" is used herein to refer to a carbocyclic aromatic system,
which may be a single ring, or multiple aromatic rings fused or linked
together as such that at least one part of the fused or linked rings forms
the conjugated aromatic system. The aryl groups include, but are not
limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl,
phenanthryl, and indane.
The term "substituted aryl" refers to aryl as just defined having one to
four substituents from the group including halogen, CN, OH, NO.sub.2,
amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted
alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio.
The term "substituted benzyl" refers to a benzyl group, having substituted
on the benzene ring, one to five substituents from the group including
halogen, CN, OH, NO.sub.2, amino, alkyl, cycloalkyl, alkenyl, alkynyl,
alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,
alkylamino, and arylthio.
The term "heterocyclic" is used herein to describe a stable 4- to
7-membered monocyclic or a stable multicyclic heterocyclic ring which is
saturated, partially unsaturated, or unsaturated, and which consists of
carbon atoms and from one to four heteroatoms selected from the group
including N, O, and S atoms. The N and S atoms may be oxidized. The
heterocyclic ring also includes any multicyclic ring in which any of above
defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring
may be attached at any heteroatom or carbon atom provided the resultant
structure is chemically stable. Such heterocyclic groups include, for
example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl,
azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl,
thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, isoquinolinyl, and tetrahydrothiopyran.
The term "substituted heterocyclic" is used herein to describe the
heterocyclic just defined having one to four substituents selected from
the group which includes halogen, CN, OH, NO.sub.2, amino, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted
alkoxy, aryloxy, substituted aryloxy, alkyloxy, substituted alkyloxy,
alkylcarbonyl, substituted alkylcarbonyl, alkylcarboxy, substituted
alkylcarboxy, alkylamino, substituted alkylamino, arylthio, or substituted
arylthio.
The term "substituted cycloalkyl" is used herein to describe a carbon-based
ring having more than 3 carbon-atoms which forms a stable ring and having
from one to five substituents selected from the group consisting of
halogen, CN, OH, NO.sub.2, amino, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy,
alkylcarbonyl, alkylcarboxy, alkylamino, substituted alkylamino, arylthio,
heterocyclic, substituted heterocyclic, aminoalkyl, and substituted
aminoalkyl.
Where the terms "substituted alkylcycloalkyl", "substituted alkylOBn",
"substituted alkylpyridyl", "substituted alkylfuranyl", "substituted alkyl
NHR.sub.7 ", "substituted alkylOH", and "substituted alkylSR.sub.8 " are
recited, the substitution may occur at the alkyl group or on the
corresponding base compound.
As used in the definition of the R.sub.4 group, an N-substituted
piperidinyl group may be defined as are the substituted heterocyclic
groups. Among particularly desirable substituents are N-alkyl-, N-aryl-,
N-acyl-, and N-sulfonyl piperidinyl groups. One particularly suitable
N-acyl-piperidinyl group is N-t-butyloxycarbonyl (BOC)-piperidine.
However, other suitable substituents can be readily identified by one of
skill in the art.
The term "alkoxy" is used herein to refer to the OR group, where R is alkyl
or substituted alkyl. The term "aryloxy" is used herein to refer to the OR
group, where R is aryl or substituted aryl. The term "alkylcarbonyl" is
used herein to refer to the RCO group, where R is alkyl or substituted
alkyl. The term "alkylcarboxy" is used herein to refer to the COOR group,
where R is alkyl or substituted alkyl. The term "aminoalkyl" refers to
both secondary and tertiary amines wherein the alkyl or substituted alkyl
groups, containing one to eight carbon atoms, which may be either same or
different and the point of attachment is on the nitrogen atom.
The term "halogen" refers to Cl, Br, F, or I.
The term "ring" structure, e.g., when R.sub.3 and R.sub.4 may form a ring
structure, includes a monocyclic structure, a bridged cyclo structure, and
fused cyclo structures, unless the type of ring structure is otherwise
specified.
The compounds of the present invention can be used in the form of salts
derived from pharmaceutically or physiologically acceptable acids or
bases. These salts include, but are not limited to, the following salts
with organic and inorganic acids such as acetic, lactic, citric, tartaric,
succinic, fumaric, maleic, malonic, mandelic, mallic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic,
toluenesulfonic and similarly known acceptable acids, and mixtures thereo
of. Other salts include salts with alkali metals or alkaline earth metals,
such as sodium (e.g., sodium hydroxide), potassium (e.g., potassium
hydroxide), calcium or magnesium.
These salts, as well as other compounds of the invention may be in the form
of esters, carbamates and other conventional "pro-drug" forms, which, when
administered in such form, convert to the active moiety in vivo. In a
currently preferred embodiment, the prodrugs are esters. See, e.g., B.
Testa and J. Caldwell, "Prodrugs Revisited: The "Ad Hoc" Approach as a
Complement to Ligand Design", Medicinal Research Reviews, 16(3):233-241,
ed., John Wiley & Sons (1996).
In one particularly desirable embodiment, the compounds of Formula (I) are
thiophenesulfonamides, and more desirably, 5-halo thiophenesulfonamides,
and most desirably, 5-halo thiophene sulfonamides with .beta.-branches in
the side chain of a primary alcohol. Thus, with respect to Formula (I),
the compound of the invention desirably has a structure in which X is S, W
is C (or CR.sub.10), Y is C (or CR.sub.10) and Z is C (or CR.sub.10), and
the sulfonamide is attached to C2 of the thiophene ring. More desirably, X
is S, W is C (or CR.sub.10), Y is C (or CR.sub.10), Z is C (or CR.sub.10)
and R.sub.6 is a halogen. Most desirably, X is S, X is C, W is C, Y is C,
Z is C, R.sub.6 is a halogen, and T is C(OH)R.sub.1 R.sub.2, where R.sub.1
and R.sub.2 are hydrogen, R.sub.3 is H, R.sub.4 is a lower alkyl of
S-stereochemistry, and R.sub.5 is H. In preliminary screening assays in
vitro and in vivo, compounds of these structures have been found to have
unexpectedly good beta-amyloid inhibitory activity, and in many cases,
better activity than compounds of Formula (I) having other heterocycles
(e.g., furans, where X is O). However, other such compounds of Formula (I)
are also useful for the purposes described herein.
For example, in another embodiment, the compounds of Formula (I) are
furansulfonamides, in which X is O, W is C, Y is C, and Z is C. In one
particularly desirable embodiment, the furansulfonamides of Formula (I)
are further characterized by .beta.-branches in the side chain of a
primary alcohol. Thus, with respect to Formula (I), in these compounds T
is C(OH)R.sub.1 R.sub.2, in which R.sub.1 and R.sub.2 are hydrogen,
R.sub.3 is H, R.sub.4 is a lower alkyl of S-stereochemistry, R.sub.5 is H
and R.sub.6 is halogen.
In still another embodiment, the compounds of Formula (I) are characterized
by being sulfonamides of Formula (I), which have .beta.-branches in the
side chain of the primary alcohol group. Thus, with respect to Formula
(I), in these compounds T is C(OH)R.sub.1 R.sub.2, R.sub.1 and R.sub.2 are
hydrogen, R.sub.3 is H, R.sub.4 is a lower alkyl of S-stereochemistry, and
R.sub.5 is H.
These and the other compounds of the invention can be prepared following
the Schemes illustrated below.
Synthesis
The compounds of the present invention can be prepared in a number of ways
well known to one skilled in the art of organic synthesis. The compounds
of the present invention can be prepared using the methods described
below, together with synthetic methods known in the synthetic organic arts
or variations of these methods by one skilled in the art. (See, generally,
Comprehensive Organic Synthesis, "Selectivity, Strategy & Efficiency in
Modem Organic Chemistry", ed., I. Fleming, Pergamon Press, New York
(1991); Comprehensive Organic Chemistry, "The Synthesis and Reactions of
Organic Compounds", ed. J. F. Stoddard, Pergamon Press, New York (1979)).
Preferred methods include, but are not limited to, those outlined below.
A first method of preparation consists of reaction of a 2-aminoalcohol II
with the appropriate sulfonyl halide in the presence of a base such as
triethylamine (TEA) and in a suitable solvent to afford compounds of
Formula III. For compounds where R.sub.2 and R.sub.1 are hydrogen,
oxidation of the N-sulfonyl primary alcohol with pyridinium chlorochromate
(PCC) or under Swern conditions then affords the corresponding aldehyde IV
which can be reacted with Grignard reagents (RMgX, where R is an
##STR4##
organic radical and X is a halogen) to afford the secondary alcohols V as a
mixture of diastereomers which can be separated by high performance liquid
chromatography (HPLC) (Scheme 1).
A second method of preparation involves reaction of an .alpha.-amino acid
or ester IX with the appropriate sulfonyl halide in the presence of a base
such as triethylamine and in a suitable solvent to afford compounds of
Formula X (Scheme 2). The intermediate N-sulfonyl acid X (Rx=H) can be
converted to the corresponding primary alcohol VIII
(R.sub.1.dbd.R.sub.2.dbd.H) utilizing standard methodology such as
LiAlH.sub.4, B.sub.2 H.sub.6 or cyanuric chloride/NaBH.sub.4. The
intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can also be reduced to the
corresponding primary alcohol VIII (R.sub.1.dbd.R.sub.2.dbd.H) utilizing
standard methodology such as LiAlH.sub.4. Alternatively, the intermediate
N-sulfonyl ester X (Rx=alkyl, Bn) can be converted to the aldehyde IV with
DiBAL. Finally, the intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can be
reacted with 2 equivalents of Grignard reagent to afford the tertiary
alcohols III with R.sub.1.dbd.R.sub.2. Alternatively, for tertiary
alcohols III with R.sub.1 not equal to R.sub.2, the corresponding Weinreb
amide (see Scheme 10) of the N-sulfonyl acid can be prepared and
##STR5##
subsequently reacted with R.sub.1 MgX and R.sub.2 MgX. For compounds of
formula X (Rx=H) that have an asymmetric center at the .alpha.-amino acid
carbon, the pure enantiomers can be obtained by standard resolution
procedures employing recrystallization of salts formed with various chiral
bases.
In a variation of the second method to prepare the primary alcohols, an
.alpha.-amino acid or ester (or N-protected derivative thereof) VI is
first converted to the corresponding primary 2-aminoalcohol VII (using the
methodology outlined in the previous paragraph), which is subsequently,
after deprotection (if necessary), reacted with the appropriate sulfonyl
halide (Scheme 3) to afford compounds of Formula VIII. For preparation of
compounds derived from unnatural .alpha.-amino acids containing beta
branching in the amino acid side chain, a method of preparation based on
the work of Hruby (Tet. Lett. 38: 5135-5138 (1997)) is outlined in Scheme
4. This route entails formation of the .alpha.,.beta.-unsaturated amide
XII of the Evans chiral auxiliary from an .alpha.,.beta.-unsaturated acid
XI, followed by conjugate addition of an organocuprate, trapping of the
resulting enolate anion XIII with NBS, displacement of the bromide XIV
with azide anion (provided by tetramethylguanidinium azide (TMGA)) to
afford
##STR6##
XV, followed by reduction to the 2-amino alcohol and subsequent
sulfonylation to afford the target compound XVI. In Schemes 1 through 4,
R.sub.5 is H.
##STR7##
For the preparation of N-alkylated sulfonamides VIII (R.sub.5 =alkyl etc.),
the sulfonamide ester XVII can be N-alkylated by either treatment with a
suitable base such as potassium carbonate followed by the alkylating agent
R.sub.5 X or by employing Mitsunobu conditions (R.sub.5 OH/DEAD, TPP).
LiBH.sub.4 reduction of the N-alkylated sulfonamide ester affords the
N-alkylated sulfonamide in the primary alcohol series VIII (Scheme 5).
These primary alcohols VIII can be converted to the secondary alcohols V
or aldehyde IV series by chemistry that has been outlined above.
Alternatively, the N-alkylated sulfonamide esters, or their corresponding
Weinreb amides, can be treated with Grignard reagents to afford the
N-alkylated tertiary alcohols III.
##STR8##
When the heterocycle attached to the sulfonamide in the above alcohols is
thiophene, the corresponding sulfone derivative XIX may be obtained by
oxidation of the thiophene compound XVIII with MCPBA (Scheme 6).
##STR9##
An alternate preparation of sulfonamides derived from unnatural
2-aminoalcohols utilizes the Bucherer modification of the Strecker
.alpha.-amino acid synthesis (Scheme 7). In this route, an aldehyde XX is
reacted with cyanide anion and ammonium carbonate to afford the hydantoin
XXI, which is hydrolyzed to the .alpha.-amino acid XXII. This compound is
then reduced to XXIII and sulfonylated to afford the desired compounds of
Formula XXIV.
##STR10##
For sulfonamides derived from 2-aminoalcohols containing an N or O
heteroatom in the side chain, a route has been devised starting from
D-serine (Scheme 8). In this route, D-serine XXV is first sulfonylated to
XXVI and subsequently converted to the ketone XXVII, which is reductively
aminated to the target compounds of Formula XXVIII.
##STR11##
For sulfonamides derived from 2-aminoalcohols in the secondary alcohol
series with R.sub.1.dbd.H and R.sub.2.dbd.CF.sub.3 (compound XXIX), a
method of preparation has been devised that is outlined in Scheme 9
starting from the aldehyde TV (prepared as in Scheme 1).
##STR12##
As has been mentioned in the section concerning Scheme 1, the preparation
of sulfonamides derived from 2-aminoalcohols in the secondary alcohol
series V results in the formation of a diastereomeric mixture. An
alternate method of preparation of these compounds that results in the
production of a pure diastereomer is outlined in Scheme 10 for compounds
derived from L-isoleucine. This method, which utilizes chemistry
previously employed by Roux (Tetrahedron 50: 5345-5360 (1994)), consists
of addition of Grignard reagents to the Weinreb amide XXX (derived from
the requisite .alpha.-amino acid) followed by stereospecific reduction of
the ketone XXXI to afford a single diastereomeric N-protected 2-amino
alcohol XXXII. Deprotection of this compound followed by reaction with
sulfonyl chlorides affords the pure diastereomeric sulfonamide secondary
alcohols of Formula XXXIII.
##STR13##
When the heterocycle attached to the sulfonamide in the above alcohols is
thiophene, the corresponding 5-iodo and 5-fluoro-thiophene derivatives may
be obtained by conversation of the 5-bromo-thiophene derivative XXXIV
(obtained as in Scheme 1) to a 5-trialkyltin-thiophene intermediate XXXV
which can be converted to either the 5-iodo-thiophene (XXXVII) by
treatment with sodium iodide and chloramine T or the 5-fluoro-thiophene
analog (XXXVI) by treatment with SELECTFLUOR.TM. (Aldrich Chemical Co)
(Scheme 11).
##STR14##
Sulfonamides derived from cyclohexylglycinol substituted by alkoxy and
amino groups at the 4 position of the cyclohexane ring can be prepared
according to the methods described herein (Scheme 12). This route entails
initial hydrogenation of 4-L-hydroxyphenylglycine XXXVIII, followed by
sulfonylation, reduction of the carboxylic acid with diborane and
formation of the N,O-acetonide XXXIX. The 4-hydroxy acetonide XXXIX is
then O-alkylated using sodium hydride and an alkylating agent such as an
alkyl or benzyl bromide. This is followed by removal of the protecting
group by treatment with aqueous acid to afford the 4-ether derivatives of
Formula XXXX. Alternatively, the 4-hydroxy acetonide XXXIX can be oxidized
to the 4-ketone which can be reductively aminated and deprotected to
afford the corresponding 4-amino analogs of Formula XXXXI.
##STR15##
Another method of preparing chirally pure N-sulfonyl 2-amino alcohols
derived from .alpha.-amino acids is outlined in Scheme 13. This method
involves construction of an Evans oxazolidone chiral auxiliary XXXXIII
from XXXXII, which is then converted to the corresponding enolate and
electrophilically aminated with trisyl azide to afford the key
intermediate XXXXIV (J. Am. Chem. Soc. 109: 6881-6883 (1987)). The azide
intermediate XXXXIV is then hydrolyzed to the .alpha.-azido acid XXXXV and
reduced to the chirally pure .alpha.-amino acid XXXXVI which can be
converted to the corresponding N-sulfonyl 2-amino alcohols by methods
previously described above (e.g. Scheme 2).
##STR16##
Finally, chirally pure .alpha.-amino acids XXXXVI, one of the possible
synthetic precursors of chiral N-sulfonyl 2-amino alcohols as mentioned
above, can also be prepared utilizing an asymmetric variant of the
Strecker .alpha.-amino acid synthesis as outlined in Scheme 14 (J. Org.
Chem. 54:1055-1062 (1989)).
##STR17##
Oximes XXXXXIV can be derived from the corresponding aldehydes IV by
standard methodology as depicted in Scheme 15.
##STR18##
Methods of Use
Compounds of Formula (I) are inhibitors of beta amyloid production. In
preliminary studies using protease specific assays, exemplary compounds of
Formula (I) have been shown to exhibit specific inhibition with respect to
protease activity. Thus, the compounds of the present invention are useful
for treatment and prevention of a variety of conditions in which
modulation of beta amyloid levels provides a therapeutic benefit. Such
conditions include, e.g., amyloid angiopathy, cerebral amyloid angiopathy,
systemic amyloidosis, Alzheimer's Disease (AD), hereditary cerebral
hemorrhage with amyloidosis of the Dutch type, inclusion body myositis,
Down's syndrome, among others.
In addition, the compounds of Formula (I) may be utilized in generating
reagents useful in diagnosis of conditions associated with abnormal levels
of beta amyloid. For example, the compounds of Formula (I) may be used to
generate antibodies, which would be useful in a variety of diagnostic
assays. Methods for generating monoclonal, polyclonal, recombinant, and
synthetic antibodies or fragments thereof, are well known to those of
skill in the art. (See, e.g., E. Mark and Padlin, "Humanization of
Monoclonal Antibodies", Chapter 4, The Handbook of Experimental
Pharmacology, Vol. 113, The Pharmacology of Monoclonal Antibodies,
Springer-Verlag (June, 1994); Kohler and Milstein and the many known
modifications thereof; PCT Patent Application No. PCT/GB85/00392; British
Patent Application Publication No. GB2188638A; Amit et al., Science,
233:747-753 (1986); Queen et al., Proc. Nat'l. Acad. Sci. USA,
86:10029-10033 (1989); International Patent Publication No. WO90/07861;
and Riechmann et al., Nature, 332:323-327 (1988); Huse et al, Science,
246:1275-1281 (1988)). Alternatively, the compounds of Formula (I) may
themselves be used in such diagnostic assays. Regardless of the reagent
selected (e.g., antibody or compound of Formula (I)), suitable diagnostic
formats including, e.g., radioimmunoassays and enzyme-linked immunosorbent
assays (ELISAs), are well known to those of skill in the art and are not a
limitation on this embodiment of the invention.
The beta amyloid inhibitory activity of many of the compounds of the
present invention has been determined using the Repressor Release Assay
(RRA). See, Table 23 below. A compound is considered active in RRA if it
leads to at least a 1.5 fold increase in luciferase activity at 20 .mu.M
and is non-toxic.
Additionally, cellular, cell-free and in vivo screening methods to detect
inhibitors of beta amyloid production are known in the art. Such assays
may include radioimmunoassays and enzyme-linked immunosorbent assay
(ELISA), among others. See, e.g., P. D. Mehta, et al., Techniques in
Diagnostic Pathology, vol. 2, eds., Bullock et al, Academic Press, Boston,
pages 99-112 (1991), International Patent Publication No. WO 98/22493,
European Patent No. 0652009, U.S. Pat. Nos. 5,703,129 and 5,593,846.
Selection of an appropriate in vitro or in vivo screening assay is not a
limitation of the present invention.
Pharmaceutical Formulation
The compounds of this invention may be administered to a subject by any
desirable route, taking into consideration the specific condition for
which it has been selected. By subject is meant any suitable mammal,
including humans, domestic animals (e.g., canines and felines), and
livestock, which have been recognized as having or at risk of having one
or more of the conditions for which modulation of beta amyloid levels is
desirable. Thus, the compounds of the invention are useful for treatment
and/or prevention of a number of human and veterinary conditions. As used
herein, "prevention" encompasses prevention of symptoms in a subject who
has been identified as at risk for the condition, but has not yet been
diagnosed with the same and/or who has not yet presented any symptoms
thereof.
These compounds may be delivered or administered by any suitable route of
delivery, e.g., oral, intravenous, subcutaneous, intramuscular,
sublingual, intracranial, epidural, intratracheal, rectal, vaginal, among
others. Most desirably, the compounds are delivered orally or by a
suitable parenteral route. The compounds may be formulated in combination
with conventional pharmaceutical carriers that are physiologically
compatible. Optionally, one or more of the compounds of the invention may
be mixed with other active agents.
Suitable physiologically compatible carriers may be readily selected by one
of skill in the art. For example, suitable solid carriers include, among
others, one or more substances which may also act as lubricants,
solubilizers, suspending agents, fillers, glidants, compression aids,
binders or tablet-disintegrating agents or an encapsulating material. In
powders, the carrier is a finely divided solid, which is in admixture with
the finely divided active ingredient. In tablets, the active ingredient is
mixed with a carrier having the necessary compression properties in
suitable proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to 99% of the active ingredient.
Suitable solid carriers include, for example, starch, sugars (including,
e.g., lactose and sucrose), dicalcium phosphate, cellulose (including,
e.g., microcrystalline cellulose, methyl cellulose, sodium caroboxymethyl
cellulose), and kaolin.
Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups and elixirs. The active ingredient of this invention can be
dissolved or suspended in a pharmaceutically acceptable liquid carrier
such as water, an organic solvent, a mixture of both or pharmaceutically
acceptable oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers, buffers,
suspending agents, thickening agents, viscosity regulators, stabilizers or
osmo-regulators. Suitable examples of liquid carriers for oral and
parenteral administration include water (particularly containing additives
as above e.g. cellulose derivatives, preferably sodium carboxymethyl
cellulose solution), alcohols (including monohydric alcohols and
polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g.,
fractionated coconut oil, arachis oil, corn oil, peanut oil, and sesame
oil). For parenteral administration the carrier can also be an oily ester
such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are
used in sterile liquid form compositions for parenteral administration.
Optionally, additives customarily employed in the preparation of
pharmaceutical compositions may be included in the compositions of the
invention. Such components include, e.g., sweeteners or other flavoring
agents, coloring agents, preservatives, and antioxidants, e.g., vitamin E,
ascorbic acid, BHT and BHA.
Liquid pharmaceutical compositions that are sterile solutions or
suspensions can be utilized by, for example, intramuscular,
intraperitoneal or subcutaneous injection. Sterile solutions can also be
administered intravenously. Oral administration may be either liquid or
solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as
tablets or capsules. In such form, the composition is sub-divided in unit
dose containing appropriate quantities of the active ingredient; the unit
dosage forms can be packaged compositions, for example packeted powders,
vials, ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself, or it
can be the appropriate number of any such compositions in package form.
As described herein, a therapeutically or prophylactically useful amount of
a compound of the invention is that amount of a compound which alleviates
the symptoms of the disease, e.g., AD, or which prevents the onset of
symptoms, or the onset of more severe symptoms. Generally, an individual
dose (i.e., per unit, e.g., tablet) of a compound of the invention may be
in the range from about 1 .mu.g/kg to about 10 g/kg, more preferably 10
mg/kg to about 5 g/kg, and most preferably about 1 mg/kg to about 200
mg/kg. Desirably, these amounts are provided on a daily basis. However,
the dosage to be used in the treatment or prevention of a specific
cognitive deficit or other condition may be subjectively determined by the
attending physician. The variables involved include the specific cognitive
deficit and the size, age and response pattern of the patient. For
example, based upon the activity profile and potency of the compounds of
this invention, a starting dose of about 10 mg per day with gradual
increase in the daily dose to about 200 mg per day may provide the desired
dosage level in the human.
Alternatively, the use of sustained delivery devices may be desirable, in
order to avoid the necessity for the patient to take medications on a
daily basis. "Sustained delivery" is defined as delaying the release of an
active agent, i.e., a compound of the invention, until after placement in
a delivery environment, followed by a sustained release of the agent at a
later time. Those of skill in the art know suitable sustained delivery
devices. Examples of suitable sustained delivery devices include, e.g.,
hydrogels (see, e.g., U.S. Pat. Nos. 5,266,325; 4,959,217; and 5,292,515),
an osmotic pump, such as described by Alza (U.S. Pat. Nos. 4,295,987 and
5,273,752) or Merck (European Patent No. 314,206), among others;
hydrophobic membrane materials, such as ethylenemethacrylate (EMA) and
ethylenevinylacetate (EVA); bioresorbable polymer systems (see, e.g.,
International Patent Publication No. WO 98/44964, Bioxid and Cellomeda;
U.S. Pat. Nos. 5,756,127 and 5,854,388); other bioresorbable implant
devices have been described as being composed of, for example, polyesters,
polyanhydrides, or lactic acid/glycolic acid copolymers (see, e.g., U.S.
Pat. No. 5,817,343 (Alkermes Inc.)). For use in such sustained delivery
devices, the compounds of the invention may be formulated as described
herein.
EXAMPLES
The following examples are provided to illustrate the production and
activity of representative compounds of the invention and to illustrate
their performance in a screening assay. One skilled in the art will
appreciate that although specific reagents and conditions are outlined in
the following examples, these reagents and conditions are not a limitation
on the present invention.
Example 1
3-Bromo-5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sul
fonamide
##STR19##
To a solution of (S)-+-isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was
added triethylamine (46 .mu.L, 0.24 mmol) and
3-bromo-5-chlorothiophene-2-sulfonyl chloride (59.2 mg, 0.2 mmol). The
solution was stirred for 8-16 h, then concentrated. The residue was
dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC.sup.1
to give Example 1 (20.3 mg).
The following compounds (Examples 1-7, Table 1) were prepared using
3-bromo-5-chlorothiophene-2-sulfonyl chloride, 5-bromothiophene-2-sulfonyl
chloride, 3-bromo-2-chlorothiophene-5-sulfonyl chloride,
5-chlorothiophene-2-sulfonyl chloride, 2,5-dichlorothiophene-3-sulfonyl
chloride, 2,3-dichlorothiophene-5-sulfonyl chloride, and
2-thiophenesulfonyl chloride and following the procedure outlined in
Example 1.
##STR20##
TABLE 1
(LCMS.sup.2 Data: Molecular ion and retention time)
RSO.sub.2 C1 (S)-(+)-isoleucinol
3-bromo-5-chlorothiophene-2-sulfonyl Example 1
chloride (377 M + H); 3.25 min
5-bromothiophene-2-sulfonyl chloride Example 2
(344 M + H); 3.01 min
3-bromo-2-chlorothiophene-5-sulfonyl Example 3
chloride (378 M + H); 3.35 min
5-chlorothiophene-2-sulfonyl chloride Example 4
(298 M + H); 2.97 min
2,5-dichlorothiophene-3-sulfonyl chloride Example 5
(332 M + H); 3.18 min
2,3-dichlorothiophene-5-sulfonyl chloride Example 6
(332 M + H); 3.33 min
2-thiophenesulfonyl chloride Example 7
(264 M + H); 2.35 min
Example 8
5-Chloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide
##STR21##
To a solution of L-valinol (25.8 mg, 0.25 mmol) in THF (3 mL) was added
triethylamine (58 .mu.L, 0.3 mmol) and 5-chlorothiophene-2-sulfonyl
chloride (54 mg, 0.25 mmol). The solution was stirred for 8 to 16 h, then
concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by
semi-preparative RP-HPLC.sup.1 to give Example 8 (19.5 mg).
The following compounds (Examples 8-10, Table 2) were prepared using
5-thiophene-2-sulfonyl chloride and 5-bromothiophenesulfonyl chloride with
L-valinol and D-valinol and following the procedure outlined in Example 8.
##STR22##
TABLE 2
(LCMS.sup.2 Data: Molecular ion and retention time)
RSO.sub.2 Cl
5-chlorothiophene-2-sulfonyl 5-bromothiophene-2-sulfonyl
Amine chloride chloride
L-valinol Example 8 Example 9
(284 M + H); 2.70 min (330 M + H); 2.75 min
D-valinol Example 10
(330 M + H); 2.75 min
Example 11
4,5-Dibromo-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamid
e
##STR23##
To a solution of (S)-(+)-2-amino-3-methyl-1-butanol (20.6 mg, 0.2 mmol) in
THF (3 mL) was added triethylamine (46 .mu.L, 0.24 mmol) and
4,5-dibromothiophene-2-sulfonyl chloride (68 mg, 0.2 mmol). The solution
was stirred for 8 to 16 h, the solvent was removed and residue purified by
RP-HPLC.sup.1 to give Example 11 (49.6 mg).
##STR24##
TABLE 3
(LCMS.sup.2 Data: Molecular ion and retention time)
NH.sub.2 CH(R.sub.1)CH.sub.2 OH
RSO.sub.2 Cl (S)-(+)-2-amino-3-methyl-1-butanol
4,5-dibromothiophene-2- Example 11
sulfonyl chloride (408 M + H); 3.22 min
Example 12
5-Chloro-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]thiophene-2-sulfonamide
##STR25##
A. Part 1
To a solution of L-cyclohexyl-glycine (48.5 mg, 0.25 mmol) in THF (2 mL)
was added lithium aluminum hydride (1 M solution in THF) (0.8 mL, 0.8
mmol) and the solution heated at 60.degree. C. for 4 h. The solution was
stirred at 25.degree. C. for 8 to 16 hours. The reaction was quenched by
addition of water (45 .mu.L), 15% aqueous sodium hydroxide (45 .mu.L) and
water (105 .mu.L) with vigorous stirring between each addition. The
mixture was then filtered and concentrated.
B. Part 2
To a solution of the residue from Part 1 in THF (3 mL) was added
triethylamine (69 .mu.L, 0.50 mmol) and 5-chlorothiophene-2-sulfonyl
chloride (54.3 mg, 0.25 mmol). The solution was stirred for 8 to 16 h, the
solvent was removed and residue purified by RP-HPLC.sup.1 to give Example
12 (25.9 mg).
The following compounds (Examples 12-17, Table 4) were prepared using
5-chlorothiophene-2-sulfonyl chloride, and 5-bromothiophene-2-sulfonyl
chloride with L-cyclohexylglycine, .beta.-methyl-DL-phenylalanine, and
L-allo-isoleucine and following the procedure outlined in Example 12.
##STR26##
TABLE 4
(LCMS.sup.2 Data: Molecular ion and retention time)
RSO.sub.2 Cl
5-chlorothiophene-2-
sulfonyl 5-bromothiophene-2-sulfonyl
Amino acid chloride chloride
L-cyclohexyl- Example 12 Example 13
glycine (324 M + H); 3.07 min (370 M + H); 3.10 min
beta-methyl- Example 14 Example 15
DL- (346 M + H); 3.05 min (392 M + H); 3.08 min
phenylalanine
L-allo- Example 16 Example 17
isoleucine (298 M + H); 2.78 min (344 M + H); 2.82 min
Example 18
5-Bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide
1,1-dioxide
##STR27##
