PCX
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 00/39111
`(51) International Patent Classification 1 :
`(11) International Publication Number:
`C07D 295/12, 401/04, 401/12, 409/14,
`401/14, A61K 31/44, 31/445
`
`A1
`
`(43) International Publication Date:
`
`6 July 2000 (06.07.00)
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(21) International Application Number:
`
`PCT/US99/29832
`
`(22) International Filing Date:
`
`15 December 1999 (15.12.99)
`
`(30) Priority Data:
`60/113,778
`
`23 December 1998 (23.12.98)
`
`US
`
`(71) Applicants (for all designated States except US): ELI LILLY
`AND COMPANY [US/US]; Lilly Corporate Center, Indi­
`anapolis, IN 46285 (US). KYLE, Jeffrey, Alan [US/US];
`10434 Collingswood Lane, Fishers, IN 46038 (US).
`
`46033 (US). MASTERS, John, Joseph [US/US]; 12047
`Flint Stone Court, Fishers, IN 46038 (US). MENDEL,
`David [US/US]; 11348 Woods Bay Lane, Indianapolis, IN
`46236 (US). MILOT, Guy [CA/US]; 2 Farrington Street,
`Foxborough, MA 02035 (US). PINEIRO-NUNEZ, Marta,
`Maria [ES/US]; 364 Thomburg Parkway, Brownsburg, IN
`46112 (US). SAWYER, Jason, Scott [US/US]; 5718 North
`Winthrop Avenue, Indianapolis,
`
`IN 46220 (US). SHUMAN,
`Robert, Theodore [US/US]; 180 Barcelona Road, Sedona,
`AZ 86336 (US). SMITH, Gerald, Floyd [US/US]; 1848 La­
`narkshire Drive, Greenwood,
`
`IN 46143 TEBBE, Anne, (US).
`
`Louise [US/US]; 6202 North Sherman Drive, Indianapo­
`lis, IN 46220 (US). TINSLEY, Jennifer, Marie [US/US];
`4542 State Road 39 North, Martinsville, IN 46151 (US).
`WEIR, Leonard, Crayton [US/US]; 6520 Englehardt Drive,
`Raleigh, NC 27613
`(US). WIKEL,
`James,
`Howard
`4068 Sunshine Way, Greenwood, IN 46142 (US). WILEY,
`Michael, Robert [US/US]; 7725 Langwood Drive, Indi­
`anapolis, IN 46268 (US). YEE, Ying, Kwong
`[US/US];
`Briarstone Trace, Carmel, IN 46033 (US).
`
`[US/US];
`
`5127
`
`(72) Inventors; and
`(75) Inventors/Applicants
`(for US only): BEIGHT, Douglas, Wade
`
`[US/US]; 3468 South County Road 600 West, Frankfort,
`IN 46041 (US). CRAFT, Trelia, Joyce [US/US]; 10404
`East 46th Street, Indianapolis, IN 46236 (US). FRAN-
`CISKOVICH, Jeffry, Bernard [US/US]; 5036 Quail Ridge
`Lane, Indianapolis, IN 46254 (US). GOODSON, Theodore,
`(74) Agents: JACKSON, Thomas, E.
`Eli al.; and Company,
`
`
`et
`Junior [US/US]; 4045 Devon Drive, Indianapolis,
`IN 46226
`Lilly Corporate Center, Indianapolis, IN 46285 (US).
`(US). HALL, Steven, Edward [US/US]; 102 Nuttal Place,
`Chapel Hill, NC 27514 (US). HERRON, David, Kent
`[US/US]; 5945 AndoverRoad,
`(US).
`46220
`Indianapolis,
`IN
`Apartment
`JOSEPH, Sajan [US/US]; 625
`Canal
`View
`Drive,
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`I, Indianapolis, IN 46202 (US). KLIMKOWSKI, Valen­
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`tine, Joseph [US/US]; 4504 Camelot Lane, Carmel, IN
`ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG,
`US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
`LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM,
`
`
`patent AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,
`BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Lilly
`
`Published
`With international search
`
`report.
`
`(54) Title: ANTITHROMBOTIC AMIDES
`
`(57) Abstract
`
`salt thereof) as defined herein, pharmaceutical
`
`This application relates to a compound of formula (I) (or a pharmaceutically acceptable
`compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.
`
`MYLAN - EXHIBIT 1009
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`C&te d'lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`1
`
`ANTITHROMBOTIC AMIDES
`
`5
`
`This application claims the benefit of U.S. Provisional
`Application No. 60/113,778, filed 23 December 1998.
`This invention relates to antithrombotic aromatic
`amides which demonstrate activity as inhibitors of factor Xa
`10 and, accordingly, which are useful anticoagulants in
`mammals. In particular it relates to aromatic amides having
`high anticoagulant activity, and antithrombotic activity.
`Thus, this invention relates to new amides which are
`inhibitors of factor Xa, pharmaceutical compositions
`15 containing the amides as active ingredients, and the use of
`the amides as anticoagulants for prophylaxis and treatment
`of thromboembolic disorders such as venous thrombosis,
`pulmonary embolism, arterial thrombosis, in particular
`myocardial ischemia, myocardial infarction and cerebral
`20 thrombosis, general hypercoagulable states and local
`hypercoagulable states, such as following angioplasty and
`coronary bypass operations, and generalized tissue injury as
`it relates to the inflammatory process. In addition, the
`antithrombotic agents are useful as anticoagulants in in
`25 vitro applications.
`The process of blood coagulation, thrombosis, is
`triggered by a complex proteolytic cascade leading to the
`formation of thrombin. Thrombin proteolytically removes
`activation peptides from the Aa-chains and the BP-chains of
`30 fibrinogen, which is soluble in blood plasma, initiating
`insoluble fibrin formation. The formation of thrombin from
`prothrombin is catalyzed by factor Xa.
`
`

`
`WO 00/39111
`
`PCT/U S99/29832
`
`2
`Anticoagulation currently is achieved by the
`administration of heparins and coumarins. Parenteral
`pharmacological control of coagulation and thrombosis is
`based on inhibition of thrombin through the use of heparins.
`5 Heparins act indirectly on thrombin by accelerating the
`inhibitory effect of endogenous antithrombin III (the main
`physiological inhibitor of thrombin). Because antithrombin
`III levels vary in plasma and because clot-bound thrombin
`seems resistant to this indirect mechanism, heparins can be
`10 an ineffective treatment. Because coagulation assays are
`believed to be associated with efficacy and with safety,
`heparin levels must be monitored with coagulation assays
`(particularly the activated partial thromboplastin time
`(APTT) assay). Coumarins impede the generation of thrombin
`15 by blocking the posttranslational gamma-carboxylation in the
`synthesis of prothrombin and other proteins of this type.
`Because of their mechanism of action, the effect of
`coumarins can only develop slowly, 6-24 hours after
`administration. Further, they are not selective
`20 anticoagulants. Coumarins also require monitoring with
`coagulation assays (particularly the prothrombin time (PT)
`assay).
`Recently, interest has grown in small synthetic
`molecules which demonstrate potent direct inhibition of
`25 thrombin and factor Xa. See, Joseph P. Vacca (Annette M.
`Doherty Section Editor), Annual Reports in Medicinal
`Chemistry, (1998), 3_3, 81-90.
`Although the heparins and coumarins are effective
`anticoagulants, there still exists a need for anticoagulants
`30 which act selectively on factor Xa or thrombin, and which,
`independent of antithrombin III, exert inhibitory action
`shortly after administration, preferably by an oral route,
`and do not interfere with lysis of blood clots, as required
`to maintain hemostasis.
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`3
`The present invention is directed to the discovery that
`the amides of the present invention, as defined below, are
`potent inhibitors of factor Xa which may have high
`bioavailability following oral administration.
`According to the invention there is provided a compound
`of formula I
`
`^Al/L1-Q1
`A ^ A|
`
`A4 | AvV
`
`I
`
`(or a pharmaceutically acceptable salt thereof) wherein:
`, A^, A^ and A^, together with the two carbons to
`which they are attached, complete a substituted benzene in
`which A^ is CR^, A^ is CR^, A^ is CR^, and A® is CR^;
`wherein
`R3 is hydrogen;
`one of R^ and R^ is hydrogen, methyl, fluoro, chloro,
`Rf02C-, or R9NH-;
`the other of R^ and R^ is hydrogen; and
`R6 is hydrogen;
`in which R^ is hydrogen. (l-4C)alkyl or benzyl; R9 is
`hydrogen, or R-hsC^-; and R-'1 is (l-4C)alkyl or dimethylamino;
`or
`
`5
`
`10
`
`15
`
`2 0
`
`A^, A^, A^ and A®, together with the two carbons to
`which they are attached, complete a substituted
`heteroaromatic ring in which
`25 (a) one of A^, A^, A5 and A® is N, and each of the others
`is CR3, CR4, CR5 or CR6, respectively;
`or
`(b) two non-adjacent residues of A3, A4, A^ and A^ are each
`N, and each of the others is CR3, CR4, CR^ or CR^,
`respectively; wherein
`each of R3, R4, R5 and R® is independently hydrogen
`or
`methyl, or one of R3, R4, R^ and R® attached to a carbon
`
`30
`
`

`
`WO 00/39111
`
`PCT/U S99/29832
`
`5
`
`4
`which is not bonded to an N-atom is chloro and the others
`are hydrogen;
`L1 is -NH-CO-, -CO-NH- or -CH2-NH- such that -lA-Q1 is
`-NH-CO-Q1 -CO-NH-Q1 or -CH2-NH-Q1;
`Q1 is phenyl, 2-furanyl, 2-thienyl, 4-thiazolyl,
`2-pyridyl, 2-naphthyl, 1,2-dihydrobenzofuran-5-yl,
`1,2-dihydrobenzofuran-6-yl, 1,2-benzisoxazol-6-yl,
`6-indolyl, 6-indolinyl, 6-indazolyl, 5-benzimidazolyl or
`5-benzotriazolyl in which the phenyl may bear one, two or
`10 three substituents at the 3-, 4- or 5-position(s)
`independently selected from halo, cyano, carbamoyl,
`aminomethyl, methyl, methoxy, difluoromethoxy,
`hydroxymethyl, formyl, vinyl, amino, hydroxy and
`3,4-methylenedioxy; and in addition the phenyl may bear a
`15 2-chloro or 2-fluoro substituent, the 2-furanyl or 2-thienyl
`may bear a chloro or methyl substituent at the 5-position;
`the 4-thiazolyl may bear an amino substituent at the
`2-position; the 2-pyridyl may bear an amino substituent at
`the 6-position; the 1,2-benzisoxazol-6-yl, 6-indolyl or
`20 6-indazolyl may bear a chloro or methyl substituent at the
`3-position; or
`-CO-Q1 is cyclopentenylcarbonyl or cyclohexenyl-
`carbonyl;
`is -NH-CH2-Q^ in which
`is
`or
`wherein
`2A
`Q
`(showing the -CH2- to which it is attached) is
`
`25
`
`-(CH2)-
`
`2A
`N-R
`
`in which
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`5
`is hydrogen, t-butyl, methylsulfonyl, -CHRyRz,
`-CHRWRX, or 4-pyridinyl (which is unsubstituted or bears a
`substituent Rv at the 2- or 3-position) wherein
`Rv is methyl, hydroxymethyl, {(1-2C)alkoxy}carbonyl;
`cyano, carbamoyl, thiocarbamoyl, or N-hydroxyamidino;
`each of Rw and Rx independently is hydrogen or
`(l-3C)normal alkyl; or -CHRWRX is 2-indanyl or (showing the
`nitrogen to which it is attached) is
`
`(N)
`
`U
`
`in which T is a single bond or methylene and U is methylene,
`ethylene, oxy, -S(0)q- (wherein q is 0, 1 or 2) or imino
`(which may bear a methyl substituent), or T is
`ethan-1,1-diyl and U is a single bond or methylene;
`RY is hydrogen or methyl; and
`Rz is isopropyl, t-butyl, (3-6C)cycloalkyl, phenyl
`(which is unsubstituted or bears one or more substituents
`independently selected from halo, methyl, methoxy and
`hydroxy), 4-quinolinyl or heteroaryl (which heteroaryl is a
`5-meitibered aromatic ring which includes one to four
`heteroatoms selected from sulfur, oxygen and nitrogen or is
`a 6-membered aromatic ring which includes one to three
`nitrogen atoms, wherein the heteroaryl is attached at carbon
`and may bear one or more methyl substituents on carbon or
`nitrogen); and
`(showing the methylene to which it is attached) is
`
`5
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`6
`
`RP
`
`//
`
`(CH2)
`
`R0
`
`in which R0 is hydrogen, halo, (l-6C)alkyl, hydroxy,
`(1-4C)alkoxy, benzyloxy or (1-4C)alkylthio; and RP is
`5 4-morpholinyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl,
`1-methoxy-1-methylethyl, 4-piperidinyl, 4-pyridinyl,
`dimethylaminosulfonyl or -J-R^ in which J is a single bond,
`methylene, carbonyl, oxy, -S(0)q- (wherein q is 0, 1 or 2),
`or -NRr- (wherein Rr is hydrogen or methyl); and R^ is
`10 (l-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl.
`As used herein, the expression a compound of formula I
`or the expression a compound of the invention includes the
`compound and any conventional prodrug thereof, as well as a
`pharmaceutically acceptable salt of said compound or
`15 prodrug.
`A pharmaceutically acceptable salt of an antithrombotic
`agent of the instant invention includes one which is an
`acid-addition salt made from a basic compound of formula I
`and an acid which provides a pharmaceutically acceptable
`20 anion, as well as a salt which is made from an acidic
`compound of formula I and a base which provides a
`pharmaceutically acceptable cation. Thus, a salt of a novel
`compound of formula I as provided herein made with an acid
`or base which affords a pharmaceutically acceptable
`25 counterion provides a particular aspect of the invention.
`Examples of such acids and bases are provided hereinbelow.
`As an additional aspect of the invention there is
`provided a pharmaceutical formulation comprising in
`association with a pharmaceutically acceptable carrier,
`30 diluent or excipient, a novel compound of formula I (or a
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`7
`pharmaceutically acceptable salt thereof) as provided in any
`of the descriptions herein.
`In addition, there is provided the use of a factor Xa
`inhibiting compound of formula I (or prodrug or salt) as
`5 described herein as an active ingredient in the manufacture
`of a medicament for use in producing an anticoagulant or
`antithrombotic effect.
`The present invention also provides a method of
`inhibiting coagulation in a mammal comprising administering
`10 to a mammal in need of treatment, a coagulation inhibiting
`dose of a factor Xa inhibiting compound of formula I having
`any of the definitions herein.
`The present invention further provides a method of
`inhibiting factor Xa comprising administering to a mammal in
`15 need of treatment, a factor Xa inhibiting dose of a
`factor Xa inhibiting compound of formula I having any of the
`definitions herein.
`Further, the present invention provides a method of
`treating a thromboembolic disorder comprising administering
`20 to a mammal in need of treatment, an effective dose of a
`factor Xa inhibiting compound of formula I having any of the
`definitions herein.
`In addition, there is provided the use of a factor Xa
`inhibiting compound of formula I having any of the
`25 definitions herein for the manufacture of a medicament for
`treatment of a thromboembolic disorder.
`As an additional feature of the invention there is
`provided a pharmaceutical formulation comprising in
`association with a pharmaceutically acceptable carrier,
`30 diluent or excipient, a prodrug of a factor Xa inhibiting
`compound of formula I (or of a pharmaceutically acceptable
`salt thereof) as provided in any of the descriptions herein.
`In this specification, the following definitions are
`used, unless otherwise described: Halo is fluoro, chloro,
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`10
`
`8
`bromo or iodo. Alkyl, alkoxy, etc. denote both straight and
`branched groups; but reference to an individual radical such
`as "propyl" embraces only the straight chain ("normal")
`radical, a branched chain isomer such as "isopropyl" being
`5 specifically denoted.
`Particular values are listed below for radicals,
`substituents, and ranges, for illustration only, and they do
`not exclude other defined values or other values within
`defined ranges for the radicals and substituents.
`For an alkyl group or the alkyl portion of an alkyl
`containing group such as, for example alkoxy, a particular
`value for (1-2C)alkyl is methyl or ethyl, and more
`particularly is methyl; for (1-3C)normal alkyl is methyl,
`ethyl or propyl; for (1-4C)alkyl is methyl, ethyl, propyl,
`15 isopropyl, butyl, isobutyl, or t-butyl, and more
`particularly is methyl, isopropyl, butyl or t-butyl; for
`(1-6C)alkyl is methyl, ethyl, propyl, butyl, pentyl or
`hexyl, and more particularly is methyl, butyl, or hexyl. A
`particular value for (3-6C)cycloalkyl is cyclopropyl,
`20 cyclobutyl, cyclopenytyl or cyclohexyl. A particular value
`for halo is bromo or chloro, and more particularly is
`chloro.
`is 4-chlorophenyl, 4-methoxy-
`A particular value for
`phenyl, 3-fluoro-4-methoxyphenyl, 5-chlorothiophen-2-yl,
`2-pyridinyl or 6-indolyl.
`A particular value for
`is
`[1-(4-pyridinyl)piperin-4-yl-
`4-(4-morpholinyl)benzylamino,
`methyl]amino, or (l-isopropylpiperidin-4-ylmethyl)amino.
`When none of A^-A^ is N, a particular set of values for
`R3-R6 is that each of R3-R6 is hydrogen; and another
`particular set of values for R3-R6 is that each of R^, R^
`and R^ is hydrogen and R^ is chloro.
`A further particular
`set of values is that A^ is N and each of A^-A® is CH.
`A particular value for -L^-Q^ is -CO-NH-Q^-.
`
`25
`
`30
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`9
`Particular species are those listed below in the
`examples, and more particularly examples 8, 9, 11, 12, 14
`and 15.
`It will be appreciated that certain compounds of
`formula I (or salts or prodrugs, etc.) may exist in, and be
`isolated in, isomeric forms, including tautomeric forms,
`cis- or trans-isomers, as well as optically active, racemic,
`or diastereomeric forms.
`It is to be understood that the
`present invention encompasses a compound of formula I in any
`of the tautomeric forms or as an a mixture thereof; or as a
`mixture of diastereomers, as well as in the form of an
`individual diastereomer, and that the present invention
`encompasses a compound of formula I as a mixture of
`enantiomers, as well as in the form of an individual
`enantiomer, any of which mixtures or form possesses
`inhibitory properties against factor Xa, it being well known
`in the art how to prepare or isolate particular forms and
`how to determine inhibitory properties against factor Xa by
`standard tests including those described below.
`In addition, a compound of formula I (or salt or
`prodrug, etc.) may exhibit polymorphism or may form a
`solvate with water or an organic solvent.
`The present
`invention also encompasses any such polymorphic form, any
`solvate or any mixture thereof.
`A prodrug of a compound of formula I may be one formed
`in a conventional manner with a functional group of the
`compound, such as with an amino, hydroxy or carboxy group.
`A compound of formula I may be prepared by processes
`which include processes known in the chemical art for the
`production of structurally analogous compounds or by a novel
`process described herein.
`A process for the preparation of
`a compound of formula I (or a pharmaceutically acceptable
`salt thereof) and novel intermediates for the manufacture of
`a compound of formula I as defined above provide further
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`
`WO 00/39111
`
`PCT/US99/29832
`
`10
`features of the invention and are illustrated by the
`following procedures in which the meanings of the generic
`radicals are as defined above, unless otherwise specified.
`It will be recognized that it may be preferred or necessary
`to prepare a compound of formula I in which a functional
`group is protected using a conventional protecting group,
`then to remove the protecting group to provide the compound
`of formula I.
`Thus, there is provided a process for preparing a
`compound of formula I (or a pharmaceutically acceptable salt
`thereof) as provided in any of the above descriptions which
`is selected from any of those described in the examples,
`including the following.
`(A)
`For a compound of formula I in which -IJI-QI, is
`-NH-CO-Q1, acylating an amine of formula II,
`
`5
`
`10
`
`15
`
`/A°
`
`, NH2
`
`3.
`^A3
`
`R2
`
`II
`
`using a corresponding acid of formula HO-CO-Q^, or an
`20 activated derivative thereof. Typical activated derivatives
`include the acid halides, activated esters, including
`4-nitrophenyl esters and those derived from coupling
`reagents.
`Typical procedures include that described at
`Example 1-D.
`For a compound of formula I in which -LA-Q! is
`(B)
`-CO-NH-Ql and (preferably) at least one of
`and A5 is N,
`substituting the group Ya of a compound of formula III
`
`25
`
`L -Q
`
`Y
`
`III
`
`

`
`WO 00/39111
`
`PCT7US99/29832
`
`11
`
`in which Ya is a conventional leaving group for nucleophilic
`aromatic substitution with an amine of formula NH2-CH2-Q2.
`As used herein, a leaving group "Ya" is a moiety which is
`displaced in an aromatic (or heteroaromatic) nucleophilic
`substitution reaction, for example a halo group (such as
`fluoro or chloro), an alkoxy group (such as methoxy), a
`sulfonate ester group (such as methylsulfonyloxy, p-toluyl-
`sulfonyloxy or trifluoromethylsulfonyloxy), or the reactive
`species derived from treating an alcohol with triphenyl-
`phospine, diethyl azodicarboxylate and triethyl amine (in a
`Mitsunobu reaction).
`The substitution may be carried out by
`heating a mixture of the reagents in a polar solvent, for
`example in ethanol in a sealed tube as described at
`Example 8-B or in dimethylformamide with cuprous bromide as
`described at example 11-B for a compound in which neither of
`and
`is N, but only A^ is N.
`(C)
`For a compound of formula I in which -lA-Ql is
`-CO-NH-Q^, acylating an amine of formula H2N-QI, or a
`deprotonated derivative thereof, using an acid of formula
`IV, or an activated derivative thereof.
`
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`20
`
`O XA
`
`OH
`|
`A" ~R2
`
`A *-> Al
`. 4
`
`IV
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`
`Typical deprotonated derivatives of the amine H2N-QI
`include, for example, that derived from treatment of the
`amine with an organomagnesium reagent, for example, with
`allylmagnesium bromide or methylmagnesium bromide. Typical
`activated derivatives include the acid halides, activated
`esters, including 4-nitrophenyl esters and those derived
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`from coupling reagents.
`Preferably, the activated acid is
`an anhydride of formula IVb,
`
`O
`
`o
`
`Q2
`
`o
`
`IVb
`
`5
`
`A typical procedure is that described at Example 12-B.
`(D)
`Alkylating an amine of formula V
`
`^a6Yl1"q1
`a|
`A4^.
`a3
`
`nh2
`
`V
`
`10
`
`directly, using a compound of formula Y-CH^-Q^, as described
`at Example 1-D, or (preferably) indirectly by reductive
`alkylation using an aldehyde of formula Q2-CHO. In the
`reductive alkylation the intermediate imine of formula VI or
`15 acid addition salt thereof
`5^ A|
`At ^l1-q1
`
`VI
`
`a4^
`a3
`
`n=ch-q2
`
`20
`
`(which provide a further aspect of the invention) may be
`formed in situ and reduced directly, or may be isolated
`prior to reduction, for example as described at Example 14-E
`where the reduction is carried out using borane trimethyl-
`amine complex in glacial acetic acid.
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`(E) For a compound of formula I in which -L^-Q^ is
`-CE^-NH-Q^-, reducing a corresponding compound of formula I
`in which -L^-QI is -CO-NH-Ql, for example using lithium
`aluminum hydride in tetrahydrofuran as described at
`5 Example 9.
`(F)
`For a compound of formula I in which R2a is
`methylsulfonyl, substituting the amino nitrogen of a
`corresponding compound of formula I in which
`is hydrogen
`using an activated derivative of methanesulfonic acid, for
`example methanesulfonyl chloride in the presence of added
`base.
`is
`(G) For a compound of formula I in which
`-CHRyR2 or -CHRWRX, alkylating the amino nitrogen of a
`corresponding compound of formula I in which R^A is hydrogen
`15 using an alkylating agent of formula Y-CHRYR2 or Y-CHRWRX
`or, preferably, reductively alkylating the amine using a
`compound of formula RV-CO-R2- or RW-CO-RX. The direct
`alkylation may be completed in a polar solvent in the
`presence of a base. The reductive alkylation conveniently
`20 is carried out, for example, using sodium cyanoborohydride
`in methanol/acetic acid as described at Example 14-G or
`using sodium triacetoxyborohydride in an inert solvent such
`as 1,2-dichloroethane along with an excess of the carbonyl
`compound and glacial acetic acid.
`(H) For a compound of formula I in which R2a is
`'4-pyridinyl (which is unsubstituted or bears a substituent
`RV at the 2- or 3-position), substituting the amino nitrogen
`of a corresponding compound of formula I in which R2a is
`hydrogen using a corresponding pyridine reagent bearing a
`30 leaving group Y at the 4-position, for example with a
`4-chloropyridine in ethanol.
`(I) For a compound of formula I in which R2a is
`4-pyridinyl in which RV is alkoxycarbonyl, esterifying a
`corresponding compound of formula I in which RV is carboxy.
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`(J)
`For a compound of formula I in which R2A ±S
`4-pyridinyl in which Rv is hydroxymethyl,
`reducing the ester
`of a corresponding compound of formula I in which Rv is
`alkoxycarbonyl.
`For a compound of formula I in which R2a is
`(K)
`4-pyridinyl in which Rv is carbamoyl,
`amidating the ester of
`a corresponding compound of formula I in which RV is
`alkoxycarbonyl.
`(L)
`For a compound of formula I in which R2A is
`adding H2S to the
`4-pyridinyl in which Rv is thiocarbamoyl,
`nitrile of a corresponding compound of formula I in which Rv
`is cyano.
`(M) For a compound of formula I in which R^A is
`4-pyridinyl in which Rv is N-hydroxyamidino, adding H2NOH to
`the nitrile of a corresponding compound of formula I in
`which Rv is cyano.
`The addition may be direct or indirect,
`such as via an imidate ester or by treating a compound in
`which Rv is thiocarbamoyl with methyl iodide to form a
`thioimidate ester, then treatment with hydroxylamine.
`For a compound of formula I in which R^A is
`(N)
`4-pyridinyl in which Rv is carboxy, decomposing the ester of
`a corresponding compound of formula I in which Rv is
`alkoxycarbonyl.
`(0)
`For a compound of formula I in which -NRsRt is
`other than amino, alkylating a corresponding compound of
`formula I in which -NRSR^ is amino using a conventional
`method.
`When Rs and R^ together are trimethylene or
`tetramethylene, a difunctional alkylating agent, such as
`1,3-dibromopropane or 1,4-dibromobutane is preferred.
`For a compound of formula I which bears -NRsRt,
`(P)
`reductively alkylating H-NR^*- using a corresponding
`compound but in which the carbon to bear the -NRsRt group
`bears an oxo group, for example, using a procedure similar
`to one of procedure (G) above.
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`(Q) For a compound of formula I in which RP is
`1-hydroxy-l-methylethyl, adding a methyl group to the
`carbonyl group of a corresponding compound of formula I in
`which RP is acetyl using an organometallic reagent such as,
`5 for example, methylmagnesium bromide.
`(R) For a compound of formula I in which RP is
`1-methoxy-l-methylethyl, treating a corresponding compound
`of formula I in which RP is 1-hydroxy-1-methylethyl with
`methanol and an acid catalyst.
`(S) For a compound of formula I in which R^ or R^ is
`amino, reducing the nitro group of a compound corresponding
`to a compound of formula I but in which R^ or R5 is nitro.
`(T) For a compound of formula I in which R^ or
`is
`R^NH- and R9 is R^1S02-, substituting the amino group of a
`15 corresponding compound of formula I in which R^ or R^ is
`amino using an activated derivative of the sulfonic acid
`RhS02-0H.
`Whereafter, for any of the above procedures, when a
`functional group is protected using a protecting group,
`20 removing the protecting group.
`Whereafter, for any of the above procedures, when a
`pharmaceutically acceptable salt of a compound of formula I
`it is obtained by reacting the basic form of a is required,
`
`basic compound of formula I with an acid affording a
`physiologically acceptable counterion or the acidic form of
`an acidic compound of formula I with a base affording a
`physiologically acceptable counterion or by any other
`conventional procedure.
`A novel intermediate or starting material compound such
`as, for example, a novel compound of formula II, III, IV or
`VI, etc., provides a further aspect of the invention,
`The
`various starting material may be made by processes which
`include processes known in the chemical art for the
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`production of structurally analogous compounds or by a novel
`process described herein or one analogous thereto.
`As mentioned above, a compound corresponding to a
`compound of formula I but in which a functional group is
`5 protected may serve as an intermediate for a compound of
`formula I. Accordingly, such a protected intermediate for a
`novel compound of formula I provides a further aspect of the
`invention. Thus, as one particular aspect of the invention,
`there is provided a compound corresponding to a novel
`10 compound of formula I as defined above in which R4 is
`hydroxy, but in which the corresponding substituent is -OPP
`in place of hydroxy, wherein PP is a phenol protecting group
`other than (l-4C)alkyl or benzyl. Phenol protecting groups
`are well known in the art, for example as described in T.W.
`15 Greene and P.G.M. Wuts, "Protecting Groups in Organic
`Synthesis" (1991). Further, PP may denote a functionalized
`resin, for example as disclosed in H.V. Meyers, et al.,
`Molecular Diversity, (1995), 1^, 13-20.
`As mentioned above, the invention includes a
`pharmaceutically acceptable salt of the factor Xa inhibiting
`A basic compound
`compound defined by the above formula I.
`of this invention possesses one or more functional groups
`sufficiently basic to react with any of a number of
`inorganic and organic acids affording a physiologically
`acceptable counterion to form a pharmaceutically acceptable
`salt.
`Acids commonly employed to form pharmaceutically
`acceptable acid addition salts are inorganic acids such as
`hydrochloric acid, hydrobromic acid, hydroiodic acid,
`sulfuric acid, phosphoric acid, and the like, and organic
`acids such as p-toluenesulfonic acid, methanesulfonic acid,
`oxalic acid, p-bromobenzenesulfonic acid, carbonic acid,
`succinic acid, citric acid, benzoic acid, acetic acid, and
`the like.
`Examples of such pharmaceutically acceptable
`salts thus are the sulfate, pyrosulfate, bisulfate, sulfite,
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`bisulfite, phosphate, monohydrogenphosphate,
`dihydrogenphosphate, metaphosphate, pyrophosphate, chloride,
`bromide, iodide, acetate, propionate, decanoate, caprylate,
`acrylate, formate, isobutyrate, caproate, heptanoate,
`5 propiolate, oxalate, malonate, succinate, suberate,
`sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-
`dioate, benzoate, chlorobenzoate, methylbenzoate,
`dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
`phthalate, sulfonate, xylenesulfonate, phenylacetate,
`10 phenylpropionate, phenylbutyrate, citrate, lactate, gamma-
`hydroxybutyrate, glycollate, tartrate, methanesulfonate,
`propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-
`sulfonate, mandelate, and the like. Preferred
`pharmaceutically acceptable acid addition salts include
`15 those formed with mineral acids such as hydrochloric acid,
`hydrobromic acid and sulfuric acid.
`For a compound of formula I which bears an acidic
`moiety, such as a carboxy group, a pharmaceutically
`acceptable salt may be made with a base which affords a
`20 pharmaceutically acceptable cation, which includes alkali
`metal salts (especially sodium and potassium), alkaline
`earth metal salts (especially calcium and magnesium),
`aluminum salts and ammonium salts, as well as salts made
`from physiologically acceptable organic bases such as
`25 triethylamine, morpholine