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`PA 1233026
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`SI
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`'C A < 1
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`HHESEt ERjE SESSeBSt
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`CC.OMlE'Ij
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark
`
`Office
`
`October 15, 2004
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO
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`PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
`FILING DATE UNDER 35 USC
`111.
`
`APPLICATION NUMBER: 60/113,778
`FILING DATE: December 23,1998
`
`By Authority of the
`COMMISSIONER OF PATENTS AND TRADEMARKS
`[/
`
`! [J :
`?T
`
`HI i
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`T MONTGOMERY/
`Certifying Officer
`
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`"l""""""1""
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`liilillHilimllltllllinlmlilinilllN
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`
`MYLAN - EXHIBIT 1010
`
`0001
`
`

`

`PATENT APPLICATION SERIAL NO.
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
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`'19/1999 HHUHTER 00000044 050840 60113778
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`FC:114
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`PTO-1556
`(5/87)
`•U.S. GPO: 1998-433-214/80404
`
`0002
`
`

`

`Modified PTO/SB/IG (6-95)
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`DEPARTMENT OF COMMERCE
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`INVENTOR(s)/APPLICANT(s)
`FIRST NAME
`MIDDLE NAME
`STATE OR FOREIGN COUNTRY)
`RESIDENCE (CITY AND EITHER
`Douglas
`Wade
`Indianapolis.
`Indiana
`Indianapolis. InHinn^
`Trelia
`.—Joyce
`Jeffry—,
`Indianapolis. Indiana
`Bernard
`.JHheodore—
`Indianapolis.
`Indiana.
`TITLE OF THE
`(280 characters
`max)
`
`w w
`
`C
`'this
`•o
`-i a
`
`LAST NAME
`Beight
`Oflft
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`OnnHsnn Jr
`
`INVENTION
`
`ANTITHROMBOTIC AMIDES
`
`37
`
`o
`t-flu
`
`jO
`!«
`
`CORRESPONDENCE ADDRESS
`
`Eli Lilly and Company
`.C. 1104
`uivis
`latent
`Lilly Corporate Center
`Indianapolis,
`Indiana 46285
`USA
`ZIP CODE
`COUNTRY
`46285
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`an agency of the United States The invention was made by an agency of the United States Government or under a contract with
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`37
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`
`0004
`
`

`

`P-11800
`
`1
`
`ANTITHROMBOTIC AMIDES
`
`Xa
`
`United
`the
`with
`37
`under
`service
`to
`addressed
`
`the
`
`5
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`10
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`15
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`20
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`25
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`30
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`35
`
`This invention relates to antithrombotic aromatic
`amides which demonstrate activity as inhibitors of factor
`and, accordingly, which are useful anticoagulants in
`In particular it relates to aromatic amides having
`mammals.
`high anticoagulant activity, and antithrombotic activity.
`Thus, this invention relates to new amides which are
`inhibitors of factor Xa, pharmaceutical compositions
`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,
`particular
`pulmonary embolism, arterial thrombosis, in
`myocardial ischemia, myocardial infarction and cerebral
`thrombosis, general hypercoagulable states and local
`hypercoagulable states, such as following angioplasty and
`coronary bypass operations, and generalized tissue injury as
`In addition, the
`it relates to the inflammatory process,
`antithrombotic agents are useful as anticoagulants in in
`vitro applications.
`The process of blood coagulation, thrombosis, is
`triggered by a complex proteolytic cascade leading to
`Thrombin proteolytically removes
`formation of thrombin.
`activation peptides from the Act-chains and the Bp-chains of
`fibrinogen, which is soluble in blood plasma, initiating
`The formation of thrombin from
`insoluble fibrin formation.
`prothrombin is catalyzed by factor Xa.
`EL042024904US
`"Express Mail" mailing label number
`Date of Deposit
`"Dorprnhpr 9^, 1 QQft
`deposited
`I hereby certify that this paper or fee is being
`Post Office to Addressee"
`Mail
`States Postal Service "Express
`is
`and
`above
`indicated
`C.F.R. 1.10 on the date
`20231.
`Commissioner for Patents, Washington, D.C.
`D'Leah R. Sanders
`Printed Name
`
`the
`
`0005
`
`

`

`P-11800
`
`• •)
`
`)
`
`5
`
`15
`
`2
`Anticoagulation currently is achieved by the
`Parenteral
`administration of heparins and coumarins.
`pharmacological control of coagulation and thrombosis is .
`based on inhibition of thrombin through the use of heparins.
`Heparins act indirectly on thrombin by accelerating the
`inhibitory effect of endogenous antithrombin III (the main
`Because antithrombin
`physiological inhibitor of thrombin).
`Ill 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
`Coumarins impede the generation of thrombin
`(APTT) assay).
`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), _33, 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.
`
`0006
`
`

`

`P-11800
`
`)
`
`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
`
`5
`
`A|
`A ^ a3
`A"
`
`^L1-Q
`
`'R2
`
`I
`
`10
`
`is hydrogen; and
`
`(or a pharmaceutically acceptable salt thereof) wherein:
`A^, A4, A5 and A®, together with the two carbons to
`which they are attached, complete a substituted benzene in
`which A3 is CR3, A4 is CR4, A5 is CR5, and A6 is CR6;
`wherein
`R3 is hydrogen;
`one of R4 and R^ is hydrogen, methyl, fluoro, chloro,
`Rf02C-, or R9NH-;
`the other of R4 and R^
`R^ is hydrogen;
`in which R^ is hydrogen, (l-4C)alkyl or benzyl; R9 is
`and R*1 is (l-4C)alkyl or dimethylamino;
`hydrogen, or RhS02-;
`or
`A3, A4, A^ and A®, together with the two carbons to
`which they are attached, complete a substituted
`heteroaromatic ring in which
`25 (a) one of A3, A4, A^ and A^ is N, and each of the others
`is CR3, CR4, CR^ or CR^, 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, R^ and R® is independently hydrogen or
`methyl, or one of R3, R4, R^ and R® attached to a carbon
`
`15
`
`20
`
`30
`
`0007
`
`

`

`P-11800
`
`'
`
`)
`
`
`
`)
`
`5
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`10
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`15
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`20
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`25
`
`4
`which is not bonded to an N-atom is chloro and the others
`are hydrogen;
`lA is -NH-CO-, -CO-NH- or -CH2-NH- such that -L^-Q^ 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
`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
`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
`6-indazolyl may bear a chloro or methyl substituent at the
`3-position; or
`-CO-Ql is cyclopentenylcarbonyl or cyclohexenyl-
`carbonyl;
`or Q^B wherein
`is
`R2 is -NH-CH2-Q2 in which
`(showing the -CH2- to which it is attached) is
`\ 2A
`N-R /
`
`-(CH2)-
`
`in which
`
`0008
`
`

`

`P-11800
`
`)
`
`5
`hydrogen, t-butyl, methylsulfonyl, -CHRVR2,
`R2A is
`-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
`(1-3C)normal alkyl; or -CHRWRX is 2-indanyl or (showing the
`nitrogen to which it is attached) is
`
`O (N)
`
`methylene,
`in which T is a single bond or methylene and U is
`(wherein q is 0, 1 or 2) or imino
`ethylene, oxy, -S(0)q-
`(which may bear a methyl substituent), or T is
`ethan-1,1-diyl and U is a single bond or methylene;
`RV is hydrogen or methyl; and
`(3-6C)cycloalkyl, phenyl
`Rz is isopropyl, t-butyl,
`(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-membered aromatic ring which includes one to four
`heteroatoms selected from sulfur, oxygen and nitrogen or is
`three
`to
`a 6-membered aromatic ring which includes one
`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
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`25
`
`0009
`
`

`

`P-11800
`
`N 1 /
`
`6
`
`(CH2) \ //
`
`Rp
`
`R0
`
`is
`
`(l-SOalkyl, hydroxy.
`is hydrogen, halo,
`in which R0
`(1-4C)alkoxy, benzyloxy or (1-4C)alkylthio; and RP
`5 4-morpholinyl, 1-hydroxyethyl, 1-hydroxy-l-methylethyl,
`1-methoxy-l-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),
`is
`or -NRr- (wherein Rr is hydrogen or methyl); and
`10 (1-6C)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
`as a
`compound and any conventional prodrug thereof, as well
`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
`
`0010
`
`

`

`P-11800
`
`any
`
`provided in
`
`7
`pharmaceutically acceptable salt thereof) as
`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
`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
`to a mammal in need of treatment, a coagulation inhibiting
`having
`formula I
`dose of a factor Xa inhibiting compound of
`any of the definitions herein.
`The present invention further provides a method of
`inhibiting factor Xa comprising administering to a mammal in
`need of treatment, a factor Xa inhibiting dose of
`a
`of the
`having any
`factor Xa inhibiting compound of formula I
`definitions herein.
`Further, the present invention provides a method of
`treating a thromboembolic disorder comprising administering
`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
`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,
`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
`Halo is fluoro, chloro.
`used, unless otherwise described:
`
`5
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`25
`
`30
`
`0011
`
`

`

`P-11800
`
`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,
`A particular value
`cyclobutyl, cyclopenytyl or cyclohexyl.
`for halo is bromo or chloro, and more particularly is
`chloro.
`A particular value for
`is 4-chlorophenyl, 4-methoxy-
`phenyl, 3-fluoro-4-methoxyphenyl, 5-chlorothiophen-2-yl,
`2-pyridinyl or 6-indolyl. A particular value for R2 is
`4-(4-morpholinyl)benzylamino, [1-(4-pyridinyl)piperin-4-yl-
`methyl]amino, or (l-isopropylpiperidin-4-ylmethyl)amino.
`When none of A^-A^ is N, a particular set of values for
`that each of R3-R6 is hydrogen; and another
`R3_R6
`particular set of values for R3-R6 is that each of R^, R5
`
`and R6 is hydrogen and R4 is chloro. A further particular
`set of values is that A^ is N and each of A4-A® is CH.
`A particular value for -L^-Q^ is -CO-NH-Q^-.
`
`30
`
`20
`
`25
`
`0012
`
`

`

`P-11800
`
`9
`the
`Particular species are those listed below in
`9, 11, 12, 14
`examples, and more particularly examples 8,
`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.
`It is to be understood that the
`or diastereomeric forms,
`present invention encompasses a compound of formula I in any
`or as a
`of the tautomeric forms or as an a mixture thereof;
`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
`The present
`solvate with water or an organic solvent,
`invention also encompasses any such polymorphic form, any
`solvate or any mixture thereof.
`may be one formed
`A prodrug of a compound of formula I
`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
`by a novel
`production of structurally analogous compounds or
`A process for the preparation of
`process described herein.
`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
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`20
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`25
`
`30
`
`0013
`
`

`

`P-11800
`
`10
`features of the invention and are illustrated by the
`generic
`following procedures in which the meanings of the
`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.
`For a compound of formula I in which -L^-Ql, is
`(A)
`-NH-CO-Ql, acylating an amine of formula II,
`
`5
`
`10
`
`15
`
`Af^
`
`NH2
`
`R2
`
`II
`
`25
`
`using a corresponding acid of formula HO-CO-Q-'-,
`an
`or
`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 -L^-Ql is
`(B)
`-CO-NH-QI anci (preferably) at least one of and A^ is N,
`substituting the group Ya of a compound of formula III
`Af^Sr-" -Q
`L1
`A6
`Y
`
`III
`
`0014
`
`

`

`P-11800
`
`-)
`
`11
`
`in which Ya is a conventional leaving group for nucleophilic
`aromatic substitution with an amine of formula NH2-CH2-Q^-
`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
`The substitution may be carried out by
`Mitsunobu reaction).
`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
`neither of
`which
`described at example 11-B for a compound in
`A3 and A5 is N, but only A^ is N.
`which -L^-Q^ is
`in
`For a compound of formula I
`(C)
`-C0-NH-Q1, acylating an amine of formula H2N-QI, or a
`formula
`acid of
`deprotonated derivative thereof, using an
`IV, or an activated derivative thereof.
`O
`X X .
`A|
`OH
`A 4
`I A3 R2
`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
`Typical
`allylmagnesium bromide or methylmagnesium bromide,
`activated derivatives include the acid halides, activated
`esters, including 4-nitrophenyl esters and those derived
`
`IV
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`0015
`
`

`

`P-11800
`
`12
`Preferably, the activated acid is
`from coupling reagents,
`an anhydride of formula IVb,
`
`A
`
`.A
`
`3 A
`
`0
`
`O
`
`N
`
`O
`
`Q2
`
`IVb
`
`5
`
`A typical procedure is that described at example 12-B.
`Alkylating an amine of formula V
`(D)
`5X -L1-Q
`NH2
`A
`
`] A4^ I A|
`
`v
`
`10
`
`directly, using a compound of formula Y-CH2-Q^, as described
`at example 1-D, or (preferably) indirectly by reductive
`alkylation using an aldehyde of formula Q^-CHO. In the
`reductive alkylation the intermediate imine of formula VI or
`15 acid addition salt thereof
`
`Af^V
`I
`A" ^N=CH-Q2
`
`A 4
`
`VI
`
`20
`
`(which provide a further aspect of the invention) may be
`be isolated
`formed in situ and reduced directly, or may
`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.
`
`0016
`
`

`

`P-11800
`
`)
`
`)
`
`10
`
`15
`
`20
`
`13
`(E) For a compound of formula I in which -L^-Q^ is
`-CH2-NH-Q1, reducing a corresponding compound of formula I
`in which -L^-Q-*- is -C0-NH-Q1, for example using lithium
`aluminum hydride in tetrahydrofuran as described at
`5 Example 9.
`is
`For a compound of formula I in which
`(F)
`substituting the amino nitrogen of a
`methylsulfonyl,
`corresponding compound of formula I in which' R2A is hydrogen
`for
`using an activated derivative of methanesulfonic acid,
`added
`example methanesulfonyl chloride in the presence of
`base.
`is
`For a compound of formula I in which
`(G)
`-CHRyR2 or -CHRWRX, alkylating the amino nitrogen of a
`corresponding compound of formula I in which R^A is hydrogen
`using an alkylating agent of formula Y-CHRYR2 or Y-CHRWRX
`or, preferably, reductively alkylating the amine using a
`The direct
`compound of formula RY-CO-R2 or Rw-CO-Rx.
`alkylation may be completed in a polar solvent in the
`The reductive alkylation conveniently
`presence of a base,
`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
`the carbonyl
`as 1,2-dichloroethane along with an excess of
`compound and glacial acetic acid.
`For a compound of formula I in which R^A is
`(H)
`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 R^A is
`hydrogen using a corresponding pyridine reagent bearing a
`leaving group Y at the 4-position, for example with a
`4-chloropyridine in ethanol.
`For a compound of formula I in which R^A is
`(I)
`is alkoxycarbonyl, esterifying a
`4-pyridinyl in which Rv
`corresponding compound of formula I in which Rv is carboxy.
`
`25
`
`30
`
`0017
`
`

`

`P-11800
`
`)
`
`)
`
`of
`
`14
`(J) For a compound of formula I in which R2A is
`4-pyridinyl in which Rv' is hydroxymethyl, reducing the ester
`of a corresponding compound of formula I in which Rv is
`alkoxycarbonyl.
`is
`(K) For a compound of formula I in which
`is carbamoyl, amidating the ester
`4-pyridinyl in which Rv
`a corresponding compound of formula I in which Rv is
`alkoxycarbonyl.
`which R^A is
`in
`(L) For a compound of formula I
`the
`4-pyridinyl in which Rv is thiocarbamoyl, adding H2S to
`in
`which Rv
`nitrile of a corresponding compound of formula I
`is cyano.
`For a compound of formula I in which R^A is
`(M)
`is N-hydroxyamidino, adding H2NOH to
`4-pyridinyl in which Rv
`the nitrile of a corresponding compound of formula I in
`The addition may be direct or indirect.
`which Rv is cyano.
`such as via an imidate ester or by treating a compound in
`is thiocarbamoyl with methyl iodide to form a
`which Rv
`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.
`For a compound of formula I in which -NRsRt is
`(0)
`other than amino, alkylating a corresponding compound of
`formula I in which -NRsRt is amino using a conventional
`When Rs and R^ together are trimethylene or
`method.
`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)
`using a corresponding
`reductively alkylating H-NRsRt
`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.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`0018
`
`

`

`P-11800
`
`)
`
`)
`
`5
`
`in
`
`10
`
`15
`
`15
`For a compound of formula I in which RP is
`( Q )
`the
`1-hydroxy-l-methylethyl, adding a methyl group to
`carbonyl group of a corresponding compound of formula I
`which RP is acetyl using an organometallic reagent such as,
`for example, methylmagnesium bromide.
`For a compound of formula I in which RP is
`( R )
`1-methoxy-l-methylethyl, treating a corresponding compound
`of formula I in which RP is 1-hydroxy-l-methylethyl with
`methanol and an acid catalyst.
`R^
`is
`For a compound of formula I in which R^ or
`(S)
`amino, reducing the nitro group of a compound corresponding
`to a compound of formula I but in which R^ or R^ is nitro.
`For a compound of formula I in which R^ or R^
`is
`(T)
`R9NH- and R9 is R^SC^-, substituting the amino group of a
`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
`is required, it is obtained by reacting the basic form of a
`basic compound of formula I with an acid affording a
`25 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
`30 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
`
`0019
`
`

`

`P-11800
`
`)
`
`15
`
`20
`
`16
`production of structurally analogous compounds or by a novel
`process described herein or one analogous thereto.
`a
`As mentioned above, a compound corresponding to
`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
`a further aspect of the
`provides
`novel compound of formula I
`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 is
`-OPP
`hydroxy, but in which the corresponding substituent is
`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.
`Organic
`Greene and P.G.M. Wuts, "Protecting Groups in
`Further, PP may denote a functionalized
`Synthesis" (1991).
`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
`Acids commonly employed to form pharmaceutically
`salt.
`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 £-toluenesulfonic acid, methanesulfonic acid,
`oxalic acid, £-bromobenzenesulfonic acid, carbonic acid,,
`succinic acid, citric acid, benzoic acid, acetic acid, and
`Examples of such pharmaceutically acceptable
`the like.
`salts thus are the sulfate, pyrosulfate, bisulfate, sulfite.
`
`25
`
`30
`
`0020
`
`

`

`P-11800
`
`17
`bisulfite, phosphate, monohydrogenphosphate,
`dihydrogenphosphate, metaphosphate, pyrophosphate, chloride,
`bromide, iodide, acetate, propionate, decanoate, caprylate,
`acrylate, formate, isobutyrate, caproate, heptanoate,
`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,
`phenylpropionate, phenylbutyrate, citrate, lactate, gamma-
`hydroxybutyrate, glycollate, tartrate, methanesulfonate,
`propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-
`Preferred
`sulfonate, mandelate, and the like.
`pharmaceutically acceptable acid addition salts include
`those formed with mineral acids such as hydrochloric acid,
`hydrobromic acid and sulfuric acid.
`acidic
`which bears an
`For a compound of formula I
`moiety, such as a carboxy group, a pharmaceutically
`acceptable salt may be made with a base which affords a
`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
`triethylamine, morpholine, piperidine and triethanolamine.
`If not commercially available, a necessary starting
`material for the preparation of a compound of formula I
`may
`be prepared by a procedure which is selected from standard
`techniques of organic chemistry, including aromatic and
`heteroaromatic substitution and transformation, from
`techniques which are analogous to the syntheses of known,
`structurally similar compounds, and techniques which are
`analo