U.S. patent application number 11/078074 was filed with the patent office on 2005-09-22 for process for preparing macrocyclic compounds.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Busacca, Carl Alan, Farina, Vittorio, Gallou, Fabrice, Haddad, Nizar, Wang, Xiao-Jun, Wei, Xudong, Xu, Jinghua, Xu, Yibo, Yee, Nathan K., Zhang, Li.
Application Number | 20050209135 11/078074 |
Document ID | / |
Family ID | 34962850 |
Filed Date | 2005-09-22 |
United States Patent
Application |
20050209135 |
Kind Code |
A1 |
Busacca, Carl Alan ; et
al. |
September 22, 2005 |
Process for preparing macrocyclic compounds
Abstract
Disclosed is a multi-step process for preparing a macrocyclic
compound of the formula (I): 1 wherein Q is a radical of the
following formula: 2 and the other variables are as defined herein.
The compounds of formula (I) are potent active agents for the
treatment of hepatitis C virus (HCV) infection.
Inventors: |
Busacca, Carl Alan;
(Poughkeepsie, NY) ; Farina, Vittorio;
(Ridgefield, CT) ; Gallou, Fabrice; (Danbury,
CT) ; Haddad, Nizar; (Danbury, CT) ; Wang,
Xiao-Jun; (Danbury, CT) ; Wei, Xudong;
(Ridgefield, CT) ; Xu, Jinghua; (Bethel, CT)
; Xu, Yibo; (New Milford, CT) ; Yee, Nathan
K.; (Danbury, CT) ; Zhang, Li; (New Milford,
CT) |
Correspondence
Address: |
MICHAEL P. MORRIS
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P O BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim
DE
|
Family ID: |
34962850 |
Appl. No.: |
11/078074 |
Filed: |
March 11, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60553317 |
Mar 15, 2004 |
|
|
|
60578123 |
Jun 8, 2004 |
|
|
|
Current U.S.
Class: |
540/456 ;
514/314; 514/4.3; 530/317; 540/465 |
Current CPC
Class: |
A61K 38/00 20130101;
C07K 5/06165 20130101; A61P 31/14 20180101; C07K 5/0802 20130101;
C07D 417/14 20130101; C07K 5/0827 20130101; C07K 1/006 20130101;
A61P 1/16 20180101; A61P 31/12 20180101 |
Class at
Publication: |
514/010 ;
514/314; 530/317; 540/465 |
International
Class: |
A61K 038/12; A61K
031/4709; C07K 005/12 |
Claims
We claim:
1. A process for preparing a compound of the following formula (I):
101wherein Q is a substituent of the following formula: 102the
olefin group attached to the cyclopropyl ring is in the
configuration syn to the A group as represented by the following
structure: 103W is N; L.sup.0 is selected from H, --OH, --OCH.sub.3
and --N(CH.sub.3).sub.2; one of L.sup.1 and L.sup.2 is --CH.sub.3,
--F, --Cl or --Br and the other of L.sup.1 and L.sup.2 is H, or
both L.sup.1 and L.sup.2 are H; R.sup.2 is 104 wherein R.sup.6 is
NH--R.sup.7 or NH--C(O)--R.sup.7, wherein R.sup.7 is independently:
C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl; R.sup.3 is
NH--C(O)--OR.sup.10, wherein R.sup.10 is C.sub.1-6 alkyl, or
C.sub.3-6 cycloalkyl; R.sup.4 is H or C.sub.1-6 alkyl; D is a
5-atom saturated alkylene chain; and A is a carboxylic acid or a
pharmaceutically acceptable salt or ester thereof; said process
comprising the step of cyclyzing a diene compound of formula (IX)
in the presence of a suitable catalyst to obtain a compound of the
formula (I): 105and when A is a protected carboxylic acid group,
optionally subjecting the compound of formula (I) to deprotection
(e.g., hydrolysis) conditions to obtain a compound of formula (I)
wherein A is a carboxylic acid group; and when A is a carboxylic
acid group in the resulting compound of formula (I), optionally
coupling this compound with a sulfonamide of formula
R.sup.11ASO.sub.2NH.sub.2 in the presence of a suitable coupling
agent, such as TBTU or HATU, to obtain a compound of formula (I)
wherein A is --C(O)--NH--SO.sub.2R A.
2. A process according to claim 1, wherein the catalyst is a
ruthenium based catalyst.
3. A process according to claim 1, wherein the reaction is carried
out in the presence of a diluent in a temperature range from about
30.degree. to about 120.degree. C.
4. A process according to claim 3, wherein the diluent is selected
from alkanes, aromatic hydrocarbons, chlorinated hydrocarbons,
ether solvents and methyl alcohol.
5. A process according to claim 1, wherein the catalyst is the
2.sup.nd generation Hoveyda's catalyst, and the reaction is carried
out at a temperature in the range of from about 90.degree. to about
108.degree. C., in the presence of an aromatic hydrocarbon diluent,
and using portionwise addition of the catalyst in the range of from
2 to 6 portions.
6. A process according to claim 1, wherein the catalyst is the
2.sup.nd generation Hoveyda's catalyst, and the reaction is carried
out at a temperature in the range of from about 30.degree. to about
45.degree. C., in the presence of a suitable activator, in a
chlorinated hydrocarbon diluent or an aromatic hydrocarbon diluent,
using a one-pot addition of catalyst or a portionwise addition of
the catalyst in the range from 2 to 4 portions.
7. A process according to claim 1, wherein the diene compound (IX)
is prepared by a process comprising the following steps: (i)
reacting a compound of the formula (II) with a compound of the
formula (III) to obtain a compound of the formula (IV): 106wherein
PG is an amino protecting group, X is a halogen atom and Q is a
substituent of the following formula: 107(ii) reacting a compound
of the formula (IV) with a compound of the formula (V) to obtain a
compound of the formula (VI): 108wherein A is an amide of formula
--C(O)--NH--R.sup.11, wherein R.sup.11 is selected from the group
consisting of: C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6 or
C.sub.10 aryl; C.sub.7-16 aralkyl and SO.sub.2R.sup.11A wherein
R.sup.11A is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl or C.sub.1-6
alkyl-C.sub.3-7 cycloalkyl; or A is a protected carboxylic acid
group; (iii) removing the nitrogen protecting group in the compound
of formula (VI) to obtain a compound of the formula (VII): 109(iv)
reacting a compound of the formula (VII) with a compound of the
formula (VIII) to obtain a compound of the formula (IX): 110wherein
W, L.sup.0, L.sup.1, L.sup.2, R.sup.2, R.sup.3, R.sup.4, D, and A
in each of the above steps are as defined in claim 1.
8. A process according to claim 1, wherein: W is N; L.sup.0 is
--OCH.sub.3; L.sup.1 is --CH.sub.3, --F, --Cl or --Br and L.sup.2
is H, or both L.sup.1 and L.sup.2 are H; R.sup.2 is 111 wherein
R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7, wherein R.sup.7 is
independently: C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl; R.sup.3 is
NH--C(O)--OR.sup.10, wherein R.sup.10 is butyl, cyclobutyl or
cyclopentyl; R.sup.4 is H or C.sub.1-3 alkyl; D is a 5-atom
saturated alkylene chain; and A is a carboxylic acid or a
pharmaceutically acceptable salt or ester thereof.
9. A compound of the following formula (IV): 112wherein PG is an
amino protecting group and Q is a substituent of the following
formula: 113wherein: W is N; L.sup.0 is selected from H, --OH,
--OCH.sub.3 and --N(CH.sub.3).sub.2; one of L.sup.1 and L.sup.2 is
--CH.sub.3, --F, --Cl or --Br and the other of L.sup.1 and L.sup.2
is H, or both L.sup.1 and L.sup.2 are H; and R.sup.2 is 114 wherein
R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7, wherein R.sup.7 is
independently: C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl.
10. A compound of formula (IV) according to claim 9, wherein: W is
N; L.sup.0 is --OCH.sub.3; L.sup.1 is --CH.sub.3, --F, --Cl or --Br
and L.sup.2 is H, or both L.sup.1 and L.sup.2 are H; R.sup.2 is 115
wherein R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7, wherein
R.sup.7 is independently: C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl;
R.sup.3 is NH--C(O)--OR.sup.10, wherein R.sup.10 is butyl,
cyclobutyl or cyclopentyl; R.sup.4 is H or C.sub.1-3 alkyl; D is a
5-atom saturated alkylene chain; and A is a carboxylic acid or a
pharmaceutically acceptable salt or ester thereof.
11. A process for preparing a compound of formula (IV) according to
claim 9, said process comprising the step of reacting a compound of
the formula (II) with a compound of the formula (III) to obtain a
compound of the formula (IV): 116wherein PG is an amino protecting
group, X is a halogen atom and Q is a substituent of the following
formula: 117wherein W, L.sup.0, L.sup.1, L.sup.2, and R.sup.2 are
as defined in claim 9.
12. A compound of the following formula (IX): 118wherein Q is a
substituent of the following formula: 119the olefin group attached
to the cyclopropyl ring is in the configuration syn to the A group
as represented by the following structure: 120W is N; L.sup.0 is
selected from H, --OH, --OCH.sub.3 and --N(CH.sub.3).sub.2; one of
L.sup.1 and L.sup.2 is --CH.sub.3, --F, --Cl or --Br and the other
of L.sup.1 and L.sup.2 is H, or both L.sup.1 and L.sup.2 are H;
R.sup.2 is 121 wherein R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7,
wherein R.sup.7 is independently: C.sub.1-6 alkyl, or C.sub.3-6
cycloalkyl; R.sup.3 is NH--C(O)--OR.sup.10, wherein R.sup.10 is
C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl; R.sup.4 is H or C.sub.1-6
alkyl; D is a 5-atom saturated alkylene chain; and A is a
carboxylic acid or a pharmaceutically acceptable salt or ester
thereof.
13. A compound of formula (IX) according to claim 12, wherein: W is
N; L.sup.0 is --OCH.sub.3; L.sup.1 is --CH.sub.3, --F, --Cl or --Br
and L.sup.2 is H, or both L.sup.1 and L.sup.2 are H; R.sup.2 is 122
wherein R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7, wherein
R.sup.7 is independently: C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl;
R.sup.3 is NH--C(O)--OR.sup.10, wherein R.sup.10 is butyl,
cyclobutyl or cyclopentyl; R.sup.4 is H or C.sub.1-3 alkyl; D is a
5-atom saturated alkylene chain; and A is a carboxylic acid or a
pharmaceutically acceptable salt or ester thereof.
Description
RELATED APPLICATIONS
[0001] Benefit of U.S. Provisional Application No. 60/553,317,
filed Mar. 15, 2004, and No. 60/578,123, filed Jun. 8, 2004, is
hereby claimed, and which are incorporated herein in their
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The invention relates to an improved process for the
preparation of macrocyclic compounds useful as agents for the
treatment of hepatitis C viral (HCV) infections.
[0004] 2. Background Information
[0005] The macrocyclic compounds of the following formula (I) and
methods for their preparation are known from: Tsantrizos et al.,
U.S. Pat. No. 6,608,027 B1; Llinas Brunet et al, U.S. Application
Publication No. 2003/0224977 A1; Llinas Brunet et al, WO
2004/037855; Llinas Brunet et al, U.S. application Ser. No.
10/945,518, filed Sep. 20, 2004; Brandenburg et al., WO 2004/092203
and Samstag et al., U.S. Application Publication No. 2004/0248779
A1: 3
[0006] wherein Q is a substituent of the following formula: 4
[0007] and the other variables are as defined herein.
[0008] The compounds of formula (I) are disclosed in the
above-mentioned patent documents as being active agents for the
treatment of hepatitis C virus (HCV) infections. The methods
disclosed for the preparation of these compounds include many
synthetic steps, which may involve protection and deprotection of
certain reactive groups. The problem addressed by the present
invention is to provide a process which allows for the manufacture
of these compounds with a minimum number of steps on a technical
scale with sufficient overall yield.
BRIEF SUMMARY OF THE INVENTION
[0009] Surprisingly, it has been found that a key ring closing
metathesis "RCM" reaction step can be carried out successfully in
the presence of the quinolone "Q" substituent that potentially
could have interfered with the catalyst activity by serving as a
ligand. Based on this discovery, it has been found that the
compounds of formula (I) described above can be prepared using
fewer synthetic steps if the synthesis is carried out using the
following general sequence of steps as described herein: 56
[0010] and when A is a protected carboxylic acid group, optionally
subjecting the compound of formula (I) to de-protection conditions
to obtain a compound of formula (I) wherein A is a carboxylic acid
group;
[0011] and when A is a carboxylic acid group in the resulting
compound of formula (I), optionally coupling this compound with a
sulfonamide of formula R.sup.11ASO.sub.2NH.sub.2 in the presence of
a suitable coupling agent, such as carbodimide reagents, TBTU or
HATU, to obtain a compound of formula (I) wherein A is
--C(O)--NH--SO.sub.2R.sup.11A.
[0012] The present invention is therefore directed to a multi-step
synthetic process for preparing compounds of formula (I) using the
synthetic sequence as described herein; particular individual steps
of this multi-step process; and particular individual intermediates
used in this multi-step process.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Definition of Terms and Conventions Used
[0014] Terms not specifically defined herein should be given the
meanings that would be given to them by one of skill in the art in
light of the disclosure and the context. As used in the
specification, however, unless specified to the contrary, the
following terms have the meaning indicated and the following
conventions are adhered to.
[0015] In the groups, radicals, or moieties defined below, the
number of carbon atoms is often specified preceding the group, for
example, C.sub.1-6 alkyl means an alkyl group or radical having 1
to 6 carbon atoms. In general, for groups comprising two or more
subgroups, the last named group is the radical attachment point,
for example, "thioalkyl" means a monovalent radical of the formula
HS-Alk-. Unless otherwise specified below, conventional definitions
of terms control and conventional stable atom valences are presumed
and achieved in all formulas and groups.
[0016] The term "C.sub.1-6 alkyl" as used herein, either alone or
in combination with another substituent, means acyclic, straight or
branched chain alkyl substituents containing from 1 to six carbon
atoms and includes, for example, methyl, ethyl, propyl, butyl,
hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, and
1,1-dimethylethyl.
[0017] The term "C.sub.3-6 cycloalkyl" as used herein, either alone
or in combination with another substituent, means a cycloalkyl
substituent containing from three to six carbon atoms and includes
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0018] The term "saturated alkylene chain" as used herein means a
divalent alkyl substituent derived by the removal of one hydrogen
atom from each end of a saturated straight or branched chain
aliphatic hydrocarbon and includes, for example,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.2CH.sub.2CH.sub.- 2--.
[0019] The term "C.sub.1-6 alkoxy" as used herein, either alone or
in combination with another substituent, means the substituent
C.sub.1-6 alkyl-O-- wherein alkyl is as defined above containing up
to six carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy,
1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter
substituent is known commonly as tert-butoxy.
[0020] The term "C.sub.3-6 cycloalkoxy" as used herein, either
alone or in combination with another substituent, means the
substituent C.sub.3-6 cycloalkyl-O-- containing from 3 to 6 carbon
atoms.
[0021] The term "C.sub.2-7 alkoxy-C.sub.1-6alkyl" as used herein,
means the substituent C.sub.2-7 alkyl-O--C.sub.1-6 alkyl wherein
alkyl is as defined above containing up to six carbon atoms.
[0022] The term "halo" as used herein means a halogen substituent
selected from bromo, chloro, fluoro or iodo.
[0023] The term "haloalkyl" as used herein means as used herein,
either alone or in combination with another substituent, means
acyclic, straight or branched chain alkyl substituents having one
or more hydrogens substituted for a halogen selected from bromo,
chloro, fluoro or iodo.
[0024] The term "thioalkyl" as used herein means as used herein,
either alone or in combination with another substituent, means
acyclic, straight or branched chain alkyl substituents containing a
thiol (HS) group as a substituent. An example of a thioalkyl group
is a thiopropyl, e.g., HS--CH.sub.2CH.sub.2CH.sub.2-- is one
example of a thiopropyl group.
[0025] The term "C.sub.6 or C.sub.10 aryl" as used herein, either
alone or in combination with another substituent, means either an
aromatic monocyclic system containing 6 carbon atoms or an aromatic
bicyclic system containing 10 carbon atoms. For example, aryl
includes a phenyl or a naphthyl ring system.
[0026] The term "C.sub.7-16 aralkyl" as used herein, either alone
or in combination with another substituent, means an aryl as
defined above linked through an alkyl group, wherein alkyl is as
defined above containing from 1 to 6 carbon atoms. Aralkyl includes
for example benzyl, and butylphenyl.
[0027] The term "Het" as used herein, either alone or in
combination with another substituent, means a monovalent
substituent derived by removal of a hydrogen from a five-, six-, or
seven-membered saturated or unsaturated (including aromatic)
heterocycle containing carbon atoms and from one to four ring
heteroatoms selected from nitrogen, oxygen and sulfur. Examples of
suitable heterocycles include: tetrahydrofuran, thiophene,
diazepine, isoxazole, piperidine, dioxane, morpholine, pyrimidine
or 7
[0028] The term "Het" also includes a heterocycle as defined above
fused to one or more other cycle be it a heterocycle or a
carbocycle, each of which may be saturated or unsaturated. One such
example includes thiazolo[4,5-b]-pyridine. Although generally
covered under the term "Het", the term "heteroaryl" as used herein
precisely defines an unsaturated heterocycle for which the double
bonds form an aromatic system. Suitable example of heteroaromatic
system include: quinoline, indole, pyridine, 8
[0029] The term "oxo" means the double-bonded group (.dbd.O)
attached as a substituent.
[0030] The term "thio" means the double-bonded group (.dbd.S)
attached as a substituent.
[0031] In general, all tautomeric forms and isomeric forms and
mixtures, whether individual geometric isomers or optical isomers
or racemic or non-racemic mixtures of isomers, of a chemical
structure or compound are intended, unless the specific
stereochemistry or isomeric form is specifically indicated in the
compound name or structure.
[0032] The term "pharmaceutically acceptable ester" as used herein,
either alone or in combination with another substituent, means
esters of the compound of formula I in which any of the carboxyl
functions of the molecule, but preferably the carboxy terminus, is
replaced by an alkoxycarbonyl function: 9
[0033] in which the R moiety of the ester is selected from alkyl
(e.g. methyl, ethyl, n-propyl, t-butyl, n-butyl); alkoxyalkyl (e.g.
methoxymethyl); alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g.
benzyl); aryloxyalkyl (e.g. phenoxymethyl); aryl (e.g. phenyl),
optionally substituted with halogen, C.sub.1-4 alkyl or C.sub.1-4
alkoxy. Other suitable prodrug esters are found in Design of
Prodrugs, Bundgaard, H. Ed. Elsevier (1985) incorporated herewith
by reference. Such pharmaceutically acceptable esters are usually
hydrolyzed in vivo when injected in a mammal and transformed into
the acid form of the compound of formula I. With regard to the
esters described above, unless otherwise specified, any alkyl
moiety present advantageously contains 1 to 16 carbon atoms,
particularly 1 to 6 carbon atoms. Any aryl moiety present in such
esters advantageously comprises a phenyl group. In particular the
esters may be a C.sub.1-16 alkyl ester, an unsubstituted benzyl
ester or a benzyl ester substituted with at least one halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro or trifluoromethyl.
[0034] The term "pharmaceutically acceptable salt" as used herein
includes those derived from pharmaceutically acceptable bases.
Examples of suitable bases include choline, ethanolamine and
ethylenediamine. Na.sup.+, K.sup.+, and Ca.sup.++ salts are also
contemplated to be within the scope of the invention (also see
Pharmaceutical Salts, Birge, S. M. et al., J. Pharm. Sci., (1977),
66, 1-19, incorporated herein by reference).
[0035] The following chemicals may be referred to by these
abbreviations:
1 Abbreviation Chemical Name ACN Acetonitrile Boc
Tert-butoxylcarbonyl DABCO 1,4-diazabicyclo[2.2.2]octane DBU
1,8-Diazabicyclo[5.4.0]undec-7-e- ne DCC
1,3-Dicyclohexylcarbodiimide DCHA Dicyclohexylamine DCM
Dichloromethane DIPEA Diisopropylethylamine or Hunigs-Base DMAP
Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO
Dimethylsulfoxide DMTMM 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium Chloride EDC
1-(3-dimethylaminopropyl)-3-ethylcarbodiinide hydrocholide HATU
O-(7-azabenzotriazol-1-yl)-N,N,',N'- tetramethyluronium
hexafluorophosphate HBTU
O-Benzotriazol-1-yl-N,N,',N'-tetramethyluronium hexafluorophosphate
HOAT 1-Hydroxy-7-azabenzotriazole HOBT 1-Hydroxybenzotriazole IPA
Isopropyl alcohol KDMO Potassium 3,7-dimethyl-3-octanoxide MCH
Methylcyclohexane MIBK 4-Methyl-2-pentanone NMP
1-Methyl-2-pyrrolidinone SEH Sodium 2-ethylhexanoate TBTU
O-(Benzotriazol-1-yl)-N,N,N',N'-tetra- methyluronium
tetrafluoroborate THF Tetrahydofuran THP Trishydroxymethylphosphine
TKC Tetrakis hydroxymethyl phosphonium chloride
Embodiments of the Invention
[0036] In the synthetic schemes below, unless specified otherwise,
all the substituent groups in the chemical formulas shall have the
same meanings as in the Formula (I). The reactants used in the
synthetic schemes described below may be obtained either as
described herein, or if not described herein, are themselves either
commercially available or may be prepared from commercially
available materials by methods known in the art. Certain starting
materials, for example, may be obtained by methods described in the
International Patent Applications WO 00/59929, WO 00/09543 and WO
00/09558, U.S. Pat. No. 6,323,180 B1 and U.S. Pat. No. 6,608,027
B1.
[0037] Optimum reaction conditions and reaction times may vary
depending on the particular reactants used. Unless otherwise
specified, solvents, temperatures, pressures, and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Typically, reaction progress may be monitored by High
Pressure Liquid Chromatography (HPLC), if desired, and
intermediates and products may be purified by chromatography on
silica gel and/or by recrystallization.
[0038] I. General Multi-Step Synthetic Method
[0039] In one embodiment, the present invention is directed to a
general multi-step synthetic method for preparing the compounds of
formula (I). Specifically, this embodiment is directed to a process
for preparing a compound of the following formula (I): 10
[0040] wherein Q is a substituent of the following formula: 11
[0041] wherein W is CH or N,
[0042] L.sup.0 is H, halo, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkoxy,
hydroxy, or N(R.sup.23).sub.2,
[0043] wherein each R.sup.23 is independently H, C.sub.1-6 alkyl or
C.sub.3-6 cycloalkyl;
[0044] L.sup.1, L.sup.2 are each independently H, halogen,
C.sub.1-4alkyl, --O-C.sub.1-4alkyl, or --S-C.sub.1-4alkyl (the
sulfur being in any oxidized state); or
[0045] L.sup.0 and L.sup.1 or
[0046] L.sup.0 and L.sup.2 may be covalently bonded to form
together with the two C-atoms to which they are linked a 4-, 5- or
6-membered carbocyclic ring wherein one or two (in the case of a 5-
or 6-membered ring)-CH.sub.2-- groups not being directly bonded to
each other, may be replaced each independently by --O-- or NR.sup.a
wherein R.sup.a is H or C.sub.1-4alkyl, and wherein said ring is
optionally mono- or di-substituted with C.sub.1-4 alkyl;
[0047] R.sup.2 is H, halo, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy,
C.sub.3-6 cycloalkoxy, C.sub.2-7 alkoxy-C.sub.1-6alkyl, C.sub.6 or
C.sub.10 aryl or Het, wherein Het is a five-, six-, or
seven-membered saturated or unsaturated heterocycle containing from
one to four heteroatoms selected from nitrogen, oxygen and
sulfur;
[0048] said cycloalkyl, aryl or Het being substituted with
R.sup.6,
[0049] wherein R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkoxy, NO.sub.2,
N(R.sup.7).sub.2, NH--C(O)--R.sup.7; or NH--C(O)--NH--R.sup.7,
wherein each R.sup.7 is independently: H, C.sub.1-6 alkyl or
C.sub.3-6 cycloalkyl;
[0050] or R.sup.6 is NH--C(O)--OR.sup.8 wherein R.sup.8 is
C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl;
[0051] R.sup.3 is hydroxy, NH.sub.2, or a group of formula
--NH--R.sup.9, wherein R.sup.9 is C.sub.6 or C.sub.10 aryl,
heteroaryl, --C(O)--R.sup.10, --C(O)--NHR.sup.10 or
--C(O)--OR.sup.10,
[0052] wherein R.sup.10 is C.sub.1-6 alkyl or C.sub.3-6
cycloalkyl;
[0053] D is a 3 to 7-atom saturated alkylene chain;
[0054] R.sup.4 is H, or from one to three substituents at any
carbon atom of said chain D, said substituent independently
selected from: C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxy, hydroxy, halo, amino, oxo, thio, and C.sub.1-6 thioalkyl;
and
[0055] A is an amide of formula --C(O)--NH--R.sup.11, wherein
R.sup.11 is selected from: C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl,
C.sub.6 or C.sub.10 aryl; C.sub.7-16 aralkyl and SO.sub.2R.sup.11A
wherein R.sup.11A is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl or
C.sub.1-6 alkyl-C.sub.3-7 cycloalkyl;
[0056] or A is a carboxylic acid or a pharmaceutically acceptable
salt or ester thereof;
[0057] said process comprising the following steps:
[0058] (i) reacting a compound of the formula (II) with a compound
of the formula (III) to obtain a compound of the formula (IV):
12
[0059] wherein PG is an amino protecting group, X is a halogen atom
and Q is a substituent of the following formula: 13
[0060] (ii) reacting a compound of the formula (IV) with a compound
of the formula (V) to obtain a compound of the formula (VI): 14
[0061] wherein A is an amide of formula --C(O)--NH--R.sup.11,
wherein R.sup.11 is selected from the group consisting of:
C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6 or C.sub.10 aryl;
C.sub.7-16 aralkyl and SO.sub.2R.sup.11A wherein R.sup.11A is
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl or C.sub.1-6 alkyl-C.sub.3-7
cycloalkyl;
[0062] or A is a protected carboxylic acid group;
[0063] (iii) removing the nitrogen protecting group in the compound
of formula (VI) to obtain a compound of the formula (VII): 15
[0064] (iv) reacting a compound of the formula (VII) with a
compound of the formula (VIII) to obtain a compound of the formula
(IX): 16
[0065] (v) cyclyzing the resulting diene compound of formula (IX)
in the presence of a suitable catalyst to obtain a compound of the
formula (I): 17
[0066] and when A is a protected carboxylic acid group, optionally
subjecting the compound of formula (I) to deprotection (e.g.,
hydrolysis) conditions to obtain a compound of formula (I) wherein
A is a carboxylic acid group;
[0067] and when A is a carboxylic acid group in the resulting
compound of formula (I), optionally coupling this compound with a
sulfonamide of formula R.sup.11ASO.sub.2NH.sub.2 in the presence of
a suitable coupling agent, such as TBTU or HATU, to obtain a
compound of formula (I) wherein A is
--C(O)--NH--SO.sub.2R.sup.11A.
[0068] II. The Individual Steps of the Synthetic Method
[0069] Additional embodiments of the invention are directed to the
individual steps of the multistep general synthetic method
described above and the individual intermediates used in these
steps. These individual steps and intermediates of the present
invention are described in detail below. All substituent groups are
as defined in the general multi-step method above.
[0070] Step (i)
[0071] This step is directed to a process for preparing a compound
of formula (IV), said process comprising reacting a compound of the
formula (II) with a compound of the formula (III): 18
[0072] The coupling reaction between the compounds of formulas (II)
and (III) is typically preformed in the presence of a base in a
suitable solvent. Examples of suitable bases for this reaction
include t-BuOK, t-BuONa, sodium bis(trimethylsilyl)amide, KDMO,
with t-BuOK being a preferred base. Examples of suitable solvents
for this reaction include polar aprotic solvents, for example,
DMSO, DMF, NMP or other common polar aprotic solvents.
[0073] The amino-protecting group PG can be any suitable
amino-protecting group that is well known in the art. See, e.g.
those described in WO 00/09543, WO 00/09558. Typical examples of
protecting groups that may be used are carbamate protecting groups
such as Boc, or CBZ groups.
[0074] The X group in formula (III) is any halogen atom, but
preferred is chlorine.
[0075] The compounds of formula (II) used as starting material are
either commercially available, e.g., Boc-4(R)-hydroxyproline, or
can be prepared from known materials using conventional techniques.
In one example, the compounds of formula (II) may be prepared by
amino-protection of the 4-hydroxyproline compounds of formula (X):
19
[0076] In the first step, an appropriate amino-protecting group is
introduced onto the ring nitrogen atom of the 4-hydroxyproline
compound of formula (X) using conventional procedures. For example,
the compound of formula (X) may be dissolved in a suitable solvent
and reacted with an appropriate amino-protecting group introducing
reagent. For example, and not intending to be limited in its scope,
when Boc (tert-butyloxycarbonyl) is the desired protecting group,
compound (X) is reacted with the anhydride Boc.sub.2O (or Boc-ON)
in a solvent mixture such as Acetone/Water, MIBK/Water or THF/Water
to which a base such as NaOH, KOH, LiOH, triethylamine,
diisopropylethylamine, or N-methyl-pyrrolidine is added, the
reaction being carried out at a temperature between 20-60.degree.
C.
[0077] The halogen-substituted quinoline compounds of formula (III)
can be prepared from the corresponding hydroxyl-susbtituted
quinoline compounds of the following formula (III') by following
well known halogenation procedures using various halogenation
reagents under a variety of conditions known in the art. Examples
of such reagents include the commonly used POX.sub.3 and PX.sub.5,
where X.dbd.F, Cl, Br or I, wherein these reagents can be used in
some cases as solvents or in combination with polar aprotic
solvents, such as DMF or Acetonitrile. 20
[0078] For examples of halogenation conditions that may be
employed, see:
[0079] Chlorination: Outt, P. E. et al, J Org Chem 1998, 63 (17),
5762-5768 and references therein;
[0080] Bromination: Nakahara, S. et al, Tetrahedron Lett 1998, 39
(31), 5521-5522 and references therein
[0081] Additional solvent: Nomoto, Y.; et al, Chem Pharm Bull 1990,
38 (8), 2179-2183.
[0082] The hydroxyl-susbtituted quinoline compounds of formula
(III') can be synthesized from commercially available materials
using the techniques described in WO 00/59929, WO 00/09543 and WO
00/09558, U.S. Pat. No. 6,323,180 B1, U.S. Pat. No. 6,608,027 B1
and U.S. Patent Application Publication No. 2005/0020503 A1.
[0083] Step (ii)
[0084] Step (ii) is directed to a process for preparing a compound
of formula (VI) said process comprising reacting a compound of the
formula (IV) with a compound of the formula (V): 21
[0085] wherein A is an amide of formula --C(O)--NH--R.sup.11,
wherein R.sup.11 is selected from the group consisting of:
C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6 or C.sub.10 aryl;
C.sub.7-16 aralkyl and SO.sub.2R.sup.11A wherein R.sup.11A is
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl or C.sub.1-6 alkyl-C.sub.3-7
cycloalkyl;
[0086] or A is a protected carboxylic acid group;
[0087] In this step, the compounds of formulas (IV) and (V) may be
linked together by well known peptide coupling techniques. See, for
example, the techniques disclosed in WO 00/09543, WO 00/09558 and
U.S. Pat. No. 6,608,027 B1. Peptide coupling between compounds of
formula (IV) and (V) could be obtained, for example, under a
variety of conditions known in the art using conventional peptide
coupling reagents such as DCC, EDC, TBTU, HBTU, HATU, DMTMM, HOBT,
or HOAT in aprotic solvents such as dichloromethane, chloroform,
THF, DMF, NMP, DMSO.
[0088] The compounds of formula (V) are known from WO 00/09543, WO
00/09558 and U.S. Pat. No. 6,608,027 B 1, and may be prepared by
techniques as described therein.
[0089] Step (iii)
[0090] Step (iii) is directed to a process for removing the
nitrogen protecting group in the compound of formula (VI) to obtain
a compound of the formula (VII): 22
[0091] This step of cleaving the nitrogen protecting group in the
compound of formula (VI) can also be accomplished by well known
techniques, e.g., as described in 00/09543, WO 00/09558 and U.S.
Pat. No. 6,608,027 B1. In particular embodiments, this process
involves the acid hydrolysis of the compound of formula (VI) with
an organic or inorganic acid, such as HCl, H.sub.2SO.sub.4, TFA,
AcOH, MeSO.sub.3H, in a variety of protic or polar nonprotic
solvents such as alcohols, ethers, ACN or DCM.
[0092] Step (iv)
[0093] Step (iv) is directed to a process for preparing a compound
of formula (IX) said process comprising reacting a compound of the
formula (VII) with a compound of the formula (VIII): 23
[0094] In this step, the compounds of formulas (VII) and (VIII) may
be linked together by the same well known peptide coupling
techniques as described above in step (ii) for the peptide coupling
of formulas (IV) and (V). Examplary conditions are the same as
described above for step (ii).
[0095] The substituted acid compound of formula (VIII) used as a
starting material are known from U.S. Pat. No. 6,608,027 B1 and may
be obtained from commercially available materials using the
techniques as described therein.
[0096] Step (v)
[0097] Step (v) is directed to a process for preparing a compound
of the formula (I) said process comprising cyclyzing the resulting
diene compound of formula (IX) in the presence of a suitable
catalyst to obtain a compound of the formula (I): 24
[0098] and when A is a protected carboxylic acid group, optionally
subjecting the compound of formula (I) to deprotection (e.g.,
hydrolysis) conditions to obtain a compound of formula (I) wherein
A is a carboxylic acid group;
[0099] and when A is a carboxylic acid group in the resulting
compound of formula (I), optionally coupling this compound with a
sulfonamide of formula R.sup.11ASO.sub.2NH.sub.2 in the presence of
a suitable coupling agent, such as TBTU or HATU, to obtain a
compound of formula (I) wherein A is
--C(O)--NH--SO.sub.2R.sup.11A.
[0100] Suitable ring-closing catalysts for this step include
ruthenium based catalysts. For example, any of the well-known
ruthenium based catalysts used in olefin metathesis reactions, such
as Grubb's catalyst (first and second generation), Hoveyda's
catalyst (first and second generation) and Nolan's catalyst, may be
used with appropriate adjustment of reaction conditions as may be
necessary to allow ring-closing to proceed, depending upon the
particular catalyst this is selected.
[0101] Suitable ruthenium catalysts for the cyclization step
include, for example, the compounds of formula A, B, C, D or E:
25
[0102] wherein
[0103] X.sup.1 and X.sup.2 each independently represent an anionic
ligand,
[0104] L.sup.1 represents a neutral electron donor ligand which is
bonded to the ruthenium atom and is optionally bonded to the phenyl
group, and
[0105] L.sup.2 represents a neutral electron donor ligand which is
bonded to the ruthenium atom; and R.sup.5 is selected from one or
more substituents on the benzene ring, each substituent
independently selected from hydrogen, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, HS--C.sub.1-6alkyl, HO--C.sub.1-6alkyl,
perfluoroC.sub.1-6alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6alkoxy,
hydroxyl, halogen, nitro, imino, oxo, thio or aryl; and
[0106] wherein X.sup.2 and L.sup.2 may optionally together form a
chelating bidentate ligand.
[0107] In a more specific embodiment, the ruthenium catalyst is a
compound of formula (A-1) or (A-2): 26
[0108] wherein:
[0109] L.sup.1 is a trisubstituted phosphine group of the formula
PR.sub.3, wherein R is selected from C.sub.1-6alkyl and
C.sub.3-8cycloalkyl,
[0110] L.sup.2 is a trisubstituted phosphine group of the formula
PR.sub.3, wherein R is selected from C.sub.1-6alkyl and
C.sub.3-8cycloalkyl,
[0111] or L.sup.2 is a group of the formula A or B: 27
[0112] wherein
[0113] R.sup.7 and R.sup.8 each independently represent a hydrogen
atom or a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.6-12 aryl or
C.sub.6-12 aryl-C.sub.1-6 alkyl group; and
[0114] R.sup.9 and R.sup.10 each independently represent a hydrogen
atom or a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.6-12 aryl or
C.sub.6-12 aryl-C.sub.1-6 alkyl group, each optionally substituted
by one, two or three groups selected from hydrogen, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, HS-C.sub.1-6alkyl, HO--C.sub.1-6alkyl,
perfluoroC.sub.1-6alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6alkoxy,
hydroxyl, halogen, nitro, imino, oxo, thio or aryl;
[0115] X.sup.1 and X.sup.2 each independently represent a halogen
atom;
[0116] R.sup.5 represent hydrogen or nitro; and
[0117] R.sup.6 represents a C.sub.1-6 alkyl group.
[0118] In another more specific embodiment, the ruthenium catalyst
is selected from:
2 28 29 30 31 32 33
[0119] where Ph is phenyl and Mes is 2,4,6-trimethylphenyl.
[0120] Ruthenium-based catalysts useful for the metathesis
cyclization step, such as those set forth above, are all known
catalysts that may be obtained by known synthetic techniques. For
example, see the following references for examples of suitable
ruthenium-based catalysts:
[0121] Organometallics 2002, 21, 671; 1999, 18, 5416; and 1998, 17,
2758;
[0122] J. Am. Chem. Soc. 2001, 123, 6543; 1999, 121, 791; 1999,
121, 2674; 2002, 124, 4954; 1998, 120, 2484; 1997, 119, 3887; 1996,
118, 100; and 1996, 118, 9606
[0123] J. Org. Chem. 1998, 63, 9904; and 1999, 64, 7202;
[0124] Angew. Chem. Int. Ed. Engl. 1998, 37, 2685; 1995, 34, 2038;
2000, 39, 3012 and 2002, 41, 4038;
[0125] U.S. Pat. Nos. 5,811,515; 6,306,987 B1; and 6,608,027 B1
[0126] In another specific embodiment of the present invention the
ring-closing reaction of step (v) is carried out in the presence of
a diluent in a temperature range from about 30.degree. to about
120.degree. C., preferably from about 90.degree. to about
108.degree. C., in particular at about 100.degree. C.
[0127] In another specific embodiment of the present invention the
ring-closing reaction of step (v) is carried out in the presence of
a diluent selected from alkanes, such as n-pentane, n-hexane or
n-heptane, aromatic hydrocarbons, such as benzene, toluene or
xylene, chlorinated hydrocarbons such as dichloromethane,
trichloromethane, tetrachloromethane or dichloroethane, ether
solvents, such as tetrahydrofuran, 2-methyl-tetrahydrofuran,
3-methyl-tetrahydrofuran, cyclopentyl methyl ether, methyl
tert-butyl ether, dimethyl ether, diethyl ether or dioxane and
methyl alcohol.
[0128] In another specific embodiment of the present invention the
ring-closing reaction of step (v) is carried out wherein the molar
ratio of the diene compound of formula IX to the catalyst ranges
from 1000:1 to 100:1, preferably from 500:1 to 110:1, in particular
from 250:1 to 150:1.
[0129] In another specific embodiment of the present invention the
ring-closing reaction of step (v) is carried out at a ratio of the
diene compound of formula IX to diluent in the range from 1:400 by
weight to 1:25 by weight, preferably from 1:200 by weight to 1:50
by weight, in particular from 1:150 by weight to 1:75 by
weight.
[0130] In another specific embodiment of the present invention the
ring-closing reaction of step (v) is carried out by portionwise
addition of the catalyst in the range from 2 to 6 portions,
preferably from 3-5 portions, in particular 4 portions.
[0131] One skilled in the art can readily optimize the cyclization
step by selecting and adjusting appropriate conditions suitable for
the particular ring-closing catalyst selected. For example,
depending upon the catalyst selected it may be preferable to run
the cyclization step at high temperature, e.g., higher than
90.degree. C., although lower temperatures may also be possible
with the addition of an activator such as copper halide (CuX, where
X is halogen) to the reaction mixture.
[0132] In another specific embodiment, this ring-closing reaction
of step (v) is performed using the 2.sup.nd generation Hoveyda's
catalyst, in a temperature range of from about 90.degree. to about
108.degree. C., for example at about 100.degree. C., in the
presence of an aromatic hydrocarbon diluent, for example toluene,
using portionwise addition of the catalyst in the range from 2 to 6
portions, for example from 3-5 portions, in particular 4
portions.
[0133] Alternatively, this ring-closing reaction of step (v) is
performed using the 2.sup.nd generation Hoveyda's catalyst, in a
temperature range of from about 30.degree. to about 45.degree. C.,
for example at about 40.degree. C., in the presence of a suitable
activator such as copper iodide, in a chlorinated hydrocarbon
diluent or an aromatic hydrocarbon diluent, for example
dichloromethane, using a one-pot addition or a portionwise addition
of the catalyst in the range from 2 to 4 portions, in particular a
one-pot addition.
[0134] In a particular embodiment of this step, the compound of
formula (IX) is dissolved in a degassed organic solvent (such as
toluene or dichloromethane) to a concentration below about 0.02M,
then treated with a ruthenium-based catalyst such as Hoveyda's
catalyst, at a temperature from about 40.degree. C. to about
110.degree. C. until completion of the reaction. Some or all of the
ruthenium metal may be removed from the reaction mixture by
treatment with a suitable heavy metal scavenger, such as THP or
other agents known to scavenge heavy metals. The reaction mixture
is washed with water, followed by partial concentration of the
organic solution (e.g., by distillation process). The organic
solution may be decolorized, such as by the addition of activated
charcoal with subsequent filtration, and then is added to a
suitable solvent at a suitable temperature, such as pre-cooled
methylcyclohexane, which causes precipitation of the product
compound of formula (I) that is collected by filtration.
[0135] When A is a carboxylic acid ester group in formula (I), the
esterified compound of formula (I) can optionally be subjected to
hydrolysis conditions to obtain the corresponding free carboxylic
acid compound. Hydrolysis can be carried out using conventional
hydrolysis conditions known in the art. In a particular embodiment,
for example, the esterified compound of formula (I) is dissolved in
an organic solvent such as THF, and a suitable hydrolyzing agent
such as lithium hydroxide monohydrate (LiOH.H.sub.2O) is added
followed by the addition of water. The resultant solution is
stirred at a temperature from about 35.degree. C. to about
50.degree. C. At the end of the reaction, the solution is cooled,
and the organic layer collected. A suitable solvent such as ethanol
is added to the organic layer and the pH is adjusted to from about
pH 5 to about pH 6. The mixture is then warmed to a temperature
from about 40.degree. C. to about 50.degree. C. at which point
water is added and solution is stirred whereupon the compound of
formula (I) begins to precipitate. Upon completion of the
precipitation, the solution is cooled to ambient temperature and
the compound of formula (I) is collected by filtration, washed and
dried.
[0136] III. Preferred Embodiments of The Compound of Formula
(I)
[0137] Preferred embodiments include compounds of formula (I) as
described above, wherein the cyclopropyl moiety R.sup.B is selected
from the 2 different diastereoisomers where the 1-carbon center of
the cyclopropyl has the R configuration as represented by
structures (i) and (ii): 34
[0138] In one specific embodiment of the compounds of formula (I),
the olefin group is in the configuration syn to the A group as
represented by structure (ii) above;
[0139] W is N;
[0140] L.sup.0 is selected from H, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OC.sub.3H.sub.7, --OCH(CH.sub.3).sub.2,
--NHCH.sub.3, --NHC.sub.2H.sub.5, --NHC.sub.3H.sub.7,
--NHCH(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
--N(CH.sub.3)C.sub.2H.sub.5, --N(CH.sub.3)C.sub.3H.s- ub.7 and
--N(CH.sub.3)CH(CH.sub.3).sub.2.
[0141] L.sup.1 and L.sup.2 are each independently selected from
hydrogen, fluorine, chlorine, bromine, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--OCH.sub.3, --OC.sub.2H.sub.5, --OC.sub.3H.sub.7 and
--OCH(CH.sub.3).sub.2,
[0142] R.sup.2 is H, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy, phenyl
or Het selected from the following: 35
[0143] wherein R.sup.6 is H, C.sub.1-6 alkyl, NH--R.sup.7,
NH--C(O)--R.sup.7, NH--C(O)--NH--R.sup.7,
[0144] wherein each R.sup.7 is independently: H, C.sub.1-6 alkyl,
or C.sub.3-6 cycloalkyl;
[0145] or R.sup.6 is NH--C(O)--OR.sup.8, wherein R.sup.8 is
C.sub.1-6 alkyl;
[0146] R.sup.3 is NH--C(O)--R.sup.10, NH--C(O)--OR.sup.10 or
NH--C(O)--NR.sup.10, wherein in each case R.sup.10 is C.sub.1-6
alkyl, or C.sub.3-6 cycloalkyl; and
[0147] D is a 4 to 6-atom saturated alkylene chain;
[0148] R.sup.4 is H or C.sub.1-6 alkyl;
[0149] and A is a carboxylic acid or a pharmaceutically acceptable
salt or ester thereof.
[0150] In another specific embodiment of the compounds of formula
(I), the olefin group is in the configuration syn to the A group as
represented by structure (ii) above;
[0151] W is N;
[0152] L.sup.0 is selected from H, --OH, --OCH.sub.3 and
--N(CH.sub.3).sub.2;
[0153] one of L.sup.1 and L.sup.2 is --CH.sub.3, --F, --Cl or --Br
and the other of L.sup.1 and L.sup.2 is H, or both L.sup.1 and
L.sup.2 are H;
[0154] R.sup.2 is 36
[0155] wherein R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7, wherein
R.sup.7 is independently: C.sub.1-6 alkyl, or C.sub.3-6
cycloalkyl;
[0156] R.sup.3 is NH--C(O)--OR.sup.10, wherein R.sup.10 is
C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl;
[0157] R.sup.4 is H or C.sub.1-6alkyl;
[0158] D is a 5-atom saturated alkylene chain; and
[0159] A is a carboxylic acid or a pharmaceutically acceptable salt
or ester thereof.
[0160] In another specific embodiment of the compounds of formula
(I), the olefin group is in the configuration syn to the A group as
represented by structure (ii) above;
[0161] W is N;
[0162] L.sup.0 is OCH.sub.3;
[0163] L.sup.1 is --CH.sub.3, --F, --Cl or --Br and and L.sup.2 is
H, or both L.sup.1 and L.sup.2 are H;
[0164] R.sup.2 is 37
[0165] wherein R.sup.6 is NH--R.sup.7 or NH--C(O)--R.sup.7, wherein
R.sup.7 is independently: C.sub.1-6 alkyl or C.sub.3-6
cycloalkyl;
[0166] R.sup.3 is NH--C(O)--OR.sup.10, wherein R.sup.10 is butyl,
cyclobutyl or cyclopentyl;
[0167] R.sup.4 is H or C.sub.1-3 alkyl;
[0168] D is a 5-atom saturated alkylene chain; and
[0169] A is a carboxylic acid or a pharmaceutically acceptable salt
or ester thereof.
[0170] The following table lists compounds representative of the
compounds of formula (I). A compound of the formula below: 38
[0171] wherein L.sup.0, L.sup.1, L.sup.2 and R.sup.2 are as defined
below:
3 Cpd # L.sup.2 L.sup.0 L.sup.1 R.sup.2 101 H --OMe Me 39 102 H
--OMe Me 40 103 H --OMe Me 41 104 H --OMe Me 42 105 H --OMe Br 43
106 H --OMe Br 44 107 H --OMe Cl 45 108 H --OMe Cl 46 109 Me --OMe
Me 47 110 Me --OMe Me 48 111 H --OMe F 49 112 H --OMe F 50 113 H
--OMe Cl 51 114 H --OMe Br 52 115 H --OMe Br 53 116 H --OMe Br
54
[0172] The following table list additional compounds representative
of the compounds of formula (I). A compound of the formula below:
55
[0173] wherein the bond from position 14 to the cyclopropyl group
is syn to the COOH, said 13,14 double is cis, R.sup.13, R.sup.4 and
R.sup.2 are defined as follows:
4 Cpd # R.sup.13: R.sup.4: R.sup.2: 201 56 H 57 202 58 H 59 203 60
H 61 204 62 H OEt; 205 63 H OEt; 206 64 H 65 207 66 H 67 208 68 H
69 209 70 H 71 210 72 H 73 211 74 H 75 212 76 H 77 213 78 H 79 214
80 H 81 215 82 H 83 216 84 H 85 217 86 H 87 218 88 H 89 219 90 H 91
220 92 10-(R)Me OEt; 221 93 H 94 222 95 H 96 223 97 H 98 and 224 99
H 100
[0174] Additional specific compounds that are representative of the
compounds of formula (I) may be found in U.S. Pat. No. 6,608,027
B1.
* * * * *