United States Patent [19] (cid:9)
`Maduskuie, Jr. et al. (cid:9)
`
`[54] N-(AMIDINOPHENYL) CYCLOUREA
`ANALOGS AS FACTOR XA INHIBITORS
`
`[75] Inventors: Thomas Peter Maduskuie, Jr.,
`Wilmington, Del.; Robert Anthony
`Galemmo, Jr., Collegeville, Pa.; Celia
`Dominguez; Mimi Lifen Quan, both of
`Newark, Del.; Karen Anita Rossi;
`Petrus Fredericus Wilhelmus Stouten,
`both of Wilmington, Del.; Jung-Hui
`Sun, Hockessin; Brian Lloyd Wells,
`Wilmington, both of Del.
`
`[73] Assignee: DuPont Pharmaceuticals Company,
`Wilmington, Del.
`
`[21] Appl. No.: 08/838,246
`
`[22] Filed: (cid:9)
`
`Apr. 16, 1997
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111111111 I
`
`US005925635A
`["1 Patent Number: (cid:9)
`[451 Date of Patent: (cid:9)
`
`5,925,635
`Jul. 20, 1999
`
`............................. (cid:9) 514/341
`7/1995 Bovy et al . (cid:9)
`5,430,043
`7/1996 Raddatz et al.......................... (cid:9) 514/326
`5,532,255
`5,612,335 3/1997 Himmelsbach et al ................. (cid:9) 514/221
`
`FOREIGN PATENT DOCUMENTS
`
`2094963 10/1993 Canada.
`2105934 3/1994 Canada.
`2169433 8/1996 Canada.
`63-243079 7/1988 Japan .
`9419329
`9/1994 WIPO.
`94 21607
`9/1994 WIPO
`95 03044
`2/1995 WIPO
`96 36639 11/1996 WIPO
`96 38421 12/1996 WIPO
`97 08150 3/1997 WIPO
`
`Primary Examiner—Yogendra N. Gupta
`Attorney, Agent, or Firm—David H. Vance
`
`[57]
`
`ABSTRACT
`
`Related U.S. Application Data
`
`The present application describes N-(amidinophenyl)
`cyclourea analogs of formula I:
`
`[60] Provisional application No. 60/015,684, Apr. 17, 1996.
`
`[51] Int. C1.6 ........................ A61K 31/55; C07D 243/10;
`C07D 487/04
`[52] U.S. Cl ........................... 514/221; 540/500; 540/502;
`540/503
`[58] (cid:9) Field of Search ............................. 514/221; 540/500,
`540/502, 503
`
`[56] (cid:9)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`II
`
`Z (cid:9)
`
`RZ
`
`D
`
`\ R (cid:9)
`
`R ~~~I )n
`
`D' N Tf N. (cid:9)
`IOI
`
`A B
`
`which are useful as inhibitors of factor Xa.
`
`5,276,049 (cid:9)
`
`1/1994 Himmelsbach et al ................. 514/392
`
`20 Claims, No Drawings
`
`MYLAN - EXHIBIT 1027
`
`

`
`5,925,635
`
`2
`
`N-(AMIDINOPHENYL) CYCLOUREA
`ANALOGS AS FACTOR XA INHIBITORS
`
`This application claims benefit of provisional application
`60/015684 filed Apr. 17, 1996.
`
`5 (cid:9)
`
`HN
`
`NHz (cid:9)
`
`Z
`1
`
`Z. (cid:9)
`
`cow
`
`B
`A ~,,/
`~Y
`Mn N X
`H
`
`FIELD OF THE INVENTION
`
`This invention relates generally to N-(amidinophenyl)
`cyclourea analogs which are inhibitors of factor Xa, phar-
`maceutical compositions containing the same, and methods
`of using the same as anticoagulant agents for treatment and
`prevention of thromboembolic disorders.
`
`BACKGROUND OF THE INVENTION
`
`Bovy et al, U.S. Pat. No. 5,430,043 describe phenyl
`amidines of the formula:
`
`NH
`II
`
`NHz (cid:9)
`
`zz
`
`Z1
`
`0 (cid:9)
`II
`
`N (cid:9)
`
`C() (cid:9)
`
`R5 R5
`
`N (cid:9)
`
`() (cid:9)
`
`R6
`
`R4 (cid:9)
`
`R3
`
`~7 (cid:9)
`
`IOI (cid:9)
`
`R2
`
`p CO
`
`which are reported to be platelet aggregation inhibitors.
`However, no mention is made of inhibiting Factor Xa.
`Himmelsbach et al, CA 2,105,934, address cyclic ureas of
`the formula:
`
`x
`Rb —N N—Ra
`Y
`
`wherein, among the multitude of choices, X may be a
`carbonyl, Y may be an C2_4 alkylene, Ra may be AB-
`C— and Rb may be —D—E—F. Group F is selected from
`—CO2R, phosphono, tetrazolyl, and R8CO—O—CHR9----
`O—CO—. The compounds described by the above formula
`are alleged to have aggregation inhibiting and/or fibrinogen
`binding properties. Factor Xa inhibiting is not discussed.
`Lam et al, WO 94/19329, report cyclic carbonyls which
`may be cyclic ureas of the formula:
`
`Rzz (cid:9)
`
`R4a (cid:9)
`
`R4 (cid:9)
`
`O
`
`R23
`~J (cid:9)
`NN~
`R7a
`
`R7
`
`5 (cid:9)
`R Rya (cid:9)
`
`a
`6 )n
`R6 R
`
`wherein at least one of R', R'°, R7, and R7" is other than
`hydrogen. Compounds of this sort are said to be useful as
`HIV protease inhibitors. N-(Amidinophenyl)cycloureas are
`not suggested as factor Xa inhibitors.
`Currie et al, WO 96/36639, set forth amidine derivatives
`of the formula:
`
`10
`
`wherein A may be a 6-membered cyclic urea, which may be
`useful as anti-platelet aggregation inhibitors. However, Y is
`15 nitrate, nitrite, or a nitric oxide donating group. The present
`compounds, in contrast, do not contain the nitric oxide
`donating groups of WO 96/36639.
`
`20 (cid:9)
`
`Klinger et al, WO 94/21607, illustrate heterocyclic com-
`pounds of the formula:
`
`25
`
`30 (cid:9)
`
`R R2
`
`Y—N (cid:9)
`
`CH2-–W
`
`Z1— N (cid:9)
`
`R3
`
`A ,Z2
`B
`
`wherein, upon judicious selection of variables, Zl may be a
`35 carbonyl, A may be NR1, R1 may be an amidino-substituted
`phenyl, and B and Z2 may each be CH2. However, the
`present compounds do not include the right-side chain
`shown above.
`
`40
`
`Mohan et al, WO 96/38421, describe N,N-di(arylmethyl)
`cyclic urea derivatives of the formula:
`
`45 (cid:9)
`
`R1 (cid:9)
`
`Rz (cid:9)
`>
`
`Rs (cid:9)
`
`r
`
`R4
`
`O (cid:9)
`
`N
`
`R8 (cid:9)
`
`R7
`
`50
`
`55
`
`wherein R7 and R8 may combine to form a benzene ring and
`the double bond shown may be absent, which may be useful
`as Factor Xa inhibitors. These compounds are preferably
`60 bis-amidino substituted. However, the presently claimed
`compounds are neither bis-benzyl nor bis-amidino substi-
`tuted.
`
`65 (cid:9)
`
`Chakravarty et al, WO 95/03044, discuss benzimidazoles
`substituted with phenoxyphenylacetic acid dervatives of the
`formula:
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`R16
`
`r~ (cid:9)
`
`R1
`
`I (cid:9)
`
``1 (cid:9)
`R1s
`
`R12
`
`N
`
`N
`
`R9
`
`3
`
`O
`
`5,925,635
`
`0
`
`5 (cid:9)
`
`D R~ (cid:9)
`
`z (cid:9)
`R2a
`
`Rz
`
`r1
`
`
`
`D
`
`Tf (cid:9) N NA\ B
`
`IOI
`
`(cid:9) —R10
`Z
`10 (cid:9)
`R1
`X-7(/
`or pharmaceutically acceptable salt or prodrug forms
`thereof, wherein A, B, R1, R2, m and n are defined below, are
`Rs (cid:9)
`Rz
`effective factor Xa inhibitors.
`
`R3b (cid:9)
`
`R3a
`
`15 (cid:9)
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`[1] Thus, in a first embodiment, the present invention
`provides novel compounds of formula I:
`
`20
`
`D
`
`\ R (cid:9)
`
`R2
`
`Rz
`
`Ra~~I )n
`
`25
`
`D (cid:9)
`
`/ N
`
`if NA ~B
`II
`O
`
`wherein R12 may be a substituted aryl group. But, this
`reference does not consider amidino-phenyl groups.
`Furthermore, the present compounds do not contain the
`above variable Z, which is defined as a carbonyl, sulfonyl,
`or phosphoryl group.
`Activated factor Xa, whose major practical role is the
`generation of thrombin by the limited proteolysis of
`prothrombin, holds a central position that links the intrinsic
`and extrinsic activation mechanisms in the final common
`pathway of blood coagulation. The generation of thrombin,
`the final serine protease in the pathway to generate a fibrin
`clot, from its precursor is amplified by formation of pro-
`thrombinase complex (factor Xa, factor V, Cat and
`phospholipid). Since it is calculated that one molecule of
`factor Xa can generate 138 molecules of thrombin (Elodi, S.,
`Varadi, K.: Optimization of conditions for the catalytic effect
`of the factor IXa factor VIII Complex: Probable role of the
`complex in the amplification of blood coagulation. Thromb.
`Res. 1979, 15, 617-629), inhibition of factor Xa may be
`more efficient that inactivation of thrombin in interrupting
`the blood coagulation system.
`Therefore, efficacious and specific inhibitors of factor Xa
`are needed as potentially valuable therapeutic agents for the
`treatment of thromboembolic disorders. It is thus desirable
`to discover new factor Xa inhibitors.
`
`35 (cid:9)
`
`or stereoisomers or pharmaceutically acceptable salt forms
`30 thereof, wherein;
`one of D and D' is selected from CN, C(=NR11)NR12R13
`NHC(=NR11)NR12R13 NR12CH(=NR11), C(0)
`NR12R13, and (CH2)~NR12R13 and the other is H;
`R1 is selected from H, (CH2),OR3, halo, Cl-, alkyl,
`(CH2),NR4R4', (CH2),CO2H, (CH2),C(=O)R4, (CH2)
`,NR4C(=O)R4, (CH2),SO2R5, and (CH2),NR4SO2R ;
`R2 is selected from H, =O, C14 alkyl substituted with 0,
`1, or 2 R', C2_6 alkenyl substituted with 0, 1, or 2 R',
`(CH2) OR3, (CH2),C(0)R4, (CH2),OC(0)R' (CH2)
`,NR3R3', (CH2),NR3C(0)R4, (CH2),SO2R5, (CH2)
`,NR3S02R5, C3_10 carbocyclic residue substituted with
`0-2 R6; and, 5-10 membered heterocyclic system
`containing from 1-3 heteroatoms selected from the
`group consisting of N, 0, and S substituted with 0-2
`R;
`R2" is absent;
`alternatively, R2 and R2" may be present on adjacent carbon
`atoms and combine to form a benzene ring substituted with
`0-2 R1° or a 5-6 membered aromatic heterocycle containing
`so 0-2 heteratoms selected from the group consisting of N, 0,
`and S and substituted with 0-2 R10a;
`R3 and R3' are independently selected from H, C14 alkyl,
`benzyl and phenyl;
`R3 and R3' may be taken together to form a 5 or 6
`membered ring substituted with 0-2 R6;
`R' and R4' are independently selected from H, OR3, C1_4
`alkyl, phenyl and NR3R3';
`R5 is selected from C14 alkyl, phenyl and NR3R3';
`Z is selected from a bond, C14 alkylene, (CH2),O(CH2)„
`(CH2)2NR3(CH2)„ (CH2),C(0)(CH2)„ (CH2),C(0)O
`(CH2)„ (CH2)20C(0)(CH2)„ (CH2),C(0)NR3(CH2)„
`(CH2)2NR3C(0)(CH2)„ (CH2)20C(0)O(CH2)„ (CH2)
`20C(0)NR3(CH2)„ (CH2)2NR3C(0)O(CH2)r, (CH2)
`2NR3C(0)NR3(CH2)„ (CH2),S(0)p(CH2)„ (CH2)
`rSO2NR3(CH2)„ (CH2)2NR3SO2(CH2)„ and (CH2)
`2NR3SO2NR3(CH2)r;
`
`40 (cid:9)
`
`45 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`SUMMARY OF THE INVENTION
`
`Accordingly, one object of the present invention is to
`provide novel N-(amidinophenyl)cyclourea factor Xa
`inhibitors or pharmaceutically acceptable salts or prodrugs
`thereof.
`
`It is another object of the present invention to provide
`pharmaceutical compositions comprising a pharmaceuti-
`cally acceptable carrier and a therapeutically effective
`amount of at least one of the compounds of the present
`invention or a pharmaceutically acceptable salt or prodrug
`form thereof.
`
`It is another object of the present invention to provide a
`method for treating thromboembolic disorders comprising
`administering to a host in need of such treatment a thera-
`peutically effective amount of at least one of the compounds
`of the present invention or a pharmaceutically acceptable
`salt or prodrug form thereof.
`
`These and other objects, which will become apparent
`during the following detailed description, have been
`achieved by the inventors' discovery that compounds of
`formula (I):
`
`

`
`5
`
`5,925,635
`
`s (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`25 (cid:9)
`
`6
`R12 is selected from H, C1_6 alkyl and (CH2)n phenyl;
`R13 is selected from H, C1_6 alkyl and (CH2)n phenyl;
`n is selected from 0, 1, 2, and 3;
`m is selected from 0 and 1;
`p is selected from 0, 1, and 2;
`q is selected from 1, 2, 3, 4, and 5; and
`r is selected from 0, 1, and 2.
`[2] In a preferred embodiment, the present invention pro-
`10 vides compounds of formula I wherein:
`D is C(=NH)NH2;
`D' is H;
`R1 is selected from H, (CH2),OR3, halo, (CH2),NR4R4',
`(CH2),CO2H, (CH2),C(=O)R4, (CH2),NR4C(=O)R4,
`(CH2),SO2R5, and (CH2),NHSO2R5;
`R2 is selected from H, =O, (CH2),OR3, (CH2),C(0)R4,
`(CH2)rOC(0)R4, (CH2),-NR3R3, (CH2)rNR3C(0)R4,
`(CH2),SO2R5, (CH2),NR3SO2R5, C3_10 carbocyclic
`residue substituted with 0-2 R6; and, 5-10 membered
`heterocyclic system containing from 1-3 heteroatoms
`selected from the group consisting of N, 0, and S
`substituted with 0-2 R6;
`R' and R4' are independently selected from H, OR3, C1_ 4
`alkyl, and NR3R3';
`R5 is selected from C1_ 4 alkyl and NR3R3';
`Z is selected from a bond, C1_ 4 alkylene, (CH2),C(0)
`(CH2)„ (CH2),C(0)NR3(CH2)„ (CH2)2NR3C(0)
`(CH2)„ (CH2)2OC(0)NR3(CH2)„ (CH2)2NR3C(0)O
`(CH2)„ (CH2)2NR3C(0)NR3(CH2)„ (CH2),S(0)p
`(CH2)„ (CH2),SO2NR3(CH2)„ (CH2)2NR3S02(CH2)„
`and (CH2)2NR3SO2NR3(CH2),; and,
`X is selected from C1_ 4 alkylene, -C(0)-, -C(0)
`CR3R3', -CR3R3'C(0)-, -C(0)O-, -C(0)
`OCR3R3', -CR3R3'C(0)O-, -OC(0)-, -OC(0)
`CR3R3" -CR3R3'OC(0)-, -S(0) - -S(0)
`PCR3R3 '-, -CR3R3'S(0)P- -S(0)2NR3-
`-C(0)NR3-, -NR3C(0)-, -NR3C(0)O-, -OC
`(0)NR3- -NR3 C(0)NR3 -, -NR3 -,
`-NR3CR3R3'- -CR3R3'NR3-, 0, -CR3R3'O-,
`and -OCR3R3'-.
`[3] In a more preferred embodiment, the present invention
`provides compounds of formula I wherein:
`R1 is selected from H, OR3, (CH2)OR3, halo, NR4R4',
`(CH2)NR4R4
`', C(=O)R', (CH2)C(=O)R4, NHC(=O)
`R4, (CH2)NHC(=O)R4, S02R5, (CH2)SO2R ,
`NHSO2R5, and (CH2)NHSO2R5;
`R2 is selected from H, =O, OR3, C(0)R', (CH2)C(0)R4,
`OC(0)R4, NR4R4', NR3C(0)R4, and NR4SO2R5;
`A is selected from:
`CS_ 6 carbocyclic residue substituted with 0-1 R6, and
`5-6 membered heterocyclic system containing from
`1-2 heteroatoms selected from the group consisting
`of N and 0 substituted with 0-1 R6;
`B is selected from: Y, X-Y, and NR2R2";
`Y is selected from one of the following carbocyclic and
`heterocyclic systems which are substituted with 0-2
`
`A is selected from:
`C3_10 carbocyclic residue substituted with 0-2 R6, and
`5-10 membered heterocyclic system containing from
`1-3 heteroatoms selected from the group consisting
`of N, 0, and S substituted with 0-2 R6;
`B is selected from:
`X-Y, NR3R3', C(0)NR3R3', SO2NR3R3',
`benzyl substituted with 0-2 R6,
`C3_10 carbocyclic residue substituted with 0-2 R6, and
`5-10 membered heterocyclic system containing from
`1-3 heteroatoms selected from the group consisting
`of N, 0, and S substituted with 0-2 R6;
`X is selected from C1_ 4 alkylene, -C(0)-, -C(0)
`CR3R3', -CR3R3'C(0)-, -C(0)O-, -C(0)
`OCR3R3'- -CR3R3'C(0)O-, -OC(0)-, -OC
`15 (cid:9)
`(0)CR3R3'-, -CR3R3'OC(0)-, -S(0)--, -S(0)
`PCR3R3 '- -CR3R3'S(0)P- -S(0)2NR3-
`-NR3S(0)2-- , -NR3S(0)2CR3R3'- -CR3R3'S(0)
`2NR3-, -NR3S(0)2NR3-, -C(0)NR3-, -NR3C
`20 (cid:9)
`(0)-, -C(0)NR3CR3R3'- -NR3C(0)CR3R3'-
`-CR3R3'C(0)NR3-, -CR3R3'NR3C(0)-, -NR3C
`(0)0-, -OC(0)NR3-, -NR3C(0)NR3-,
`-NR3-, -NR3CR3R3'-, -CR3R3'NR3-, 0,
`-CR3R3'O-, -OCR3R3'-, S, -CR3R3'S-, and
`-SCR3R3'-;
`Y is selected from:
`Ci_, alkyl substituted with 0-2 R6
`C3.10 carbocyclic residue substituted with 0-2 R6, and
`5-10 membered heterocyclic system containing from
`1-3 heteroatoms selected from the group consisting
`of N, 0, and S substituted with 0-2 R6;
`R6 is selected from H, OH, CF3, (CH2)OR3, halo, Ci_,
`alkyl, CN, NO2, (CH2),NR3R3', (CH2),C(0)R3, NR3C
`(0)R3 NR3 C(0)NR3 R3" SO2NR3 R3 "
`NR3SO2NR3R3', NR3SOz C1_, alkyl, S02-phenyl,
`and NR3SO2R8;
`R' is selected from:
`C3_10 carbocyclic residue substituted with 0-2 R6; and,
`5-10 membered heterocyclic system containing from
`1-3 heteroatoms selected from the group consisting
`of N, 0, and S substituted with 0-2 R6;
`R8 is selected from:
`C3_10 carbocyclic residue substituted with 0-2 R9; and,
`5-10 membered heterocyclic system containing from
`1-3 heteroatoms selected from the group consisting
`of N, 0, and S substituted with 0-2 R9;
`R9 is selected from H, OH, (CH2),BOR3, halo, Ci_, alkyl,
`CN, NO2, (CH2),NR3R3', (CH2),C(0)R3, NR3C(0)R3',
`NR3C(0)NR3R3', SO2NR3R3', NR3SO2NR3R3', and
`NR3SOz C1_, alkyl;
`R1° is selected from H, OR3, halo, C1_ 4 alkyl, CN, NO2,
`NR3R3', NR3C(0)R3', NR3C(0)OR3', NR3SO2-phenyl,
`and NR3SOz C1_ 4 alkyl;
`R10 a if a substituent on nitrogen is selected from H and
`C1_ 4 alkyl;
`R10 a if a substituent on carbon is selected from H, C1_ 4
`alkyl, NR3R3', NR3C(0)R3', NR3C(0)OR3', NR3SO2-
`phenyl, and NR3SOz C1_ 4 alkyl;
`R11 is selected from H, OH, C1 _ 6 alkyl, C1_ 6
`alkylcarbonyl, C1_ 6 alkoxy, C1_ 4 alkoxycarbonyl, C6.10
`aryloxy, C6.10 aryloxycarbonyl, C6.10
`arylmethylcarbonyl, C1_ 4 alkylcarbonyloxy C1_ 4
`alkoxycarbonyl, C6.10 arylcarbonyloxy C1.4
`alkoxycarbonyl, C1 _ 6 alkylaminocarbonyl,
`phenylaminocarbonyl, and phenyl C1_ 4 alkoxycarbo-
`nyl;
`
`40 (cid:9)
`
`45 (cid:9)
`
`s0 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl,
`furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl,
`thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,
`oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole,
`1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-
`oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,
`5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-
`triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran,
`
`

`
`5,925,635
`
`7
`benzothiofuran, indole, benzoxazole, benzthiazole,
`indazole, benzisoxazole, benzisothiazole,
`isoindazole, and benzothiadiazole;
`Y may also be selected from the following bicyclic
`heteroaryl ring systems:
`
`
`5 (cid:9)
`
`Ra
`
`N (cid:9)
`
`K
`
`/~Ra (cid:9)
`N (cid:9)
`
`Ra
`N (cid:9)
`\ (cid:9)
`g (cid:9)
`
`
`
`N
`
`a
`R
`
` Ra
`
`N\ a
`NR
` N
`
`K
`
`
`
`tK
`
`
`
`K
`N ~~/ K
`
`a ~~RN ~ NRa
` Oc4,
` /
`
`
`Ra
`
`K (cid:9)
`
`N and
`
`K>
`
`
`
`K is selected from 0, S, NH, and N;
`Xis selected from —CHz , —C(0)--, —C(0)CHR3—,
`—CHR3C(0)—, —S(0)P—, —S(0),CR3R3'—,
`—CHR3S(0)P , —S(0)2NR3—, —C(0)NR3—,
`—NR3C(0)—, —NR3—, —NR3CHR3—, and
`—CHR3NR3;
`R6 is selected from H, OH, CF3, (CH2),OR3, halo, Ci_,
`alkyl, CN, NO2, (CH2),NR3R3', (CH2),C(0)R3, NR3C
`(0)R3', SO2NR3R3', S02-phenyl, NR3SOz Ci_, alkyl,
`and NR3SO2R8;
`R8 is selected from:
`CS_6 carbocyclic residue substituted with 0-2 R9; and,
`5-6 membered heterocyclic system containing from
`1-3 heteroatoms selected from the group consisting
`of N, 0, and S substituted with 0-2 R9;
`R9 is selected from H, OH, (CH2),OR3, halo, Ci_, alkyl,
`CN, NO2, (CH2),NR3R3', (CH2),C(0)R3, NR3C(0)R3',
`NR3C(0)NR3R3', SO2NR3R3', NR3SO2NR3R3', and
`NR3SOz Ci_, alkyl; and,
`p is 2.
`[4] In an even more preferred embodiment, the present
`invention provides compounds of formula I wherein:
`Z is selected from a bond, C14 alkylene, (CH2),C(0)
`(CH2)„ (CH2),C(0)NR3(CH2)„ (CH2)2NR3C(0)
`(CH2)„ (CH2)2NR3C(0)NR3(CH2)„ and (CH2),S
`(CH2)„
`Xis selected from —CHz , —C(0)--, —C(0)CHR3—,
`—CHR3C(0)—, —S(0)P—, —S(0)PCR3R3'—,
`—CHR3S(0)P , —S(0)2NR3—, —C(0)NR3—, and
`—NR3C(0)—;
`R6 is selected from H, OH, CF3, (CH2),OR3, halo, C14
`alkyl, CN, NO2, (CH2),NR3R3', (CH2),C(0)R3, NR3C
`(0)R3', SO2NR3R3', S02-phenyl, and NR3SOz Ci_,
`alkyl;
`m is 1; and,
`r is selected from 0 and 1.
`[5] In a further preferred embodiment, the present invention
`provides compounds of formula I wherein:
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`8
`R3 and R3' are independently selected from H and C14
`alkyl;
`Z is selected from a bond, C14 alkylene, (CH2),C(0)NR3
`(CH2)„ (CH2)2NR3C(0)(CH2)„ and (CH2)2NR C(0)
`NR3(CH2),;
`A is selected from phenyl substituted with 0-1 R6 and a
`6 membered heterocyclic system containing 1 N and
`0-1 0 atoms and substituted with 0-1 R6;
`X is selected from —CHz , —S(0)--, —S(0)
`PCR3R3'—, —S(0)2NR3—, —C(0)NR —, and;
`Y is selected from phenyl, i-propyl, quinolynyl,
`thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl,
`cyclohexyl, and naphthyl, each of which is substituted
`with 0-2 R6; and,
`n is selected from 0, 1, and 2.
`[6] In an even further preferred embodiment, the present
`invention provides compounds of formula I wherein:
`R3 and R3' are independently selected from H and methyl;
`Z is selected from a bond, CH2, —CH2CH2-- ,
`—CH2CH2CH2-- and —CH2CH2CH2CH2 ;
`A is selected from phenyl substituted with 0-1 R6, and
`piperidinyl substituted with 0-1 R6; and,
`n is 2.
`[7] In a particularly preferred embodiment, the present
`25 invention provides compounds selected from:
`N-(3-amidinophenyl)-N'-((4-((2-sulphonamido)phenyl)
`phenyl)methyl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)
`cycloheptylurea;
`3o N-(3-amidinophenyl)-N'-(1-(picolin-2-yl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(picolin-3-yl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(picolin-4-yl)piperidin-4-yl)
`35 cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(a-phenethyl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)-
`piperidin-4-yl)cycloheptylurea;
`ao N-(3-amidinophenyl)-N'-(1-(phenyl)sulfonylpiperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinopheny1)-N'-(1-(quinolin-8-y1)
`sulfonylpiperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(2-fluorophenyl)
`45 sulfonylpiperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(l-(4-acetamidophenyl)
`sulfonylpiperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)
`sulfonylpiperidin-4-yl)cycloheptylurea;
`5o N-(3-amidinophenyl)-N'-(1-(3-aminophenyl)
`sulfonylpiperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(4-aminophenyl)
`sulfonylpiperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-((2-aminophenyl)methane)
`55 sulfonyl)piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-((2-acetamido-phenyl)methane)
`sulfonylpiperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-((thiophen-2-yl)sulfonyl)
`piperidin-4-yl)cycloheptylurea;
`6o N-(3-amidinophenyl)-N'-(l -((5-chlorothiophen-2-yl)
`sulfonyl)piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(l -((5-carbomethoxythiophen-2-
`yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-((benzo-2,1,3-thiadiazo-4-yl)
`65 sulfonyl)piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(l-((cyclohexyl)sulfamido)
`piperidin-4-yl)cycloheptylurea;
`
`(cid:9)
`(cid:9)
`

`
`5,925,635
`
`10
`
`5 (cid:9)
`
`R1
`
`/ N \
`
`D
`
`
`10
`
`N n N\Z~ A\B
`N
`NA
`T
`
`9
`N-(3-amidinophenyl)-N'-(l-((isopropyl)sulfamido)
`piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(l-((phenyl)sulfamido)piperidin-
`4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(l-((isopropyl)sulfonyl)-piperidin-
`4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(l -((5-amino-4-methylthiazol-2-
`yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-((5-acetamido-4-methylthiazol-
`2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(1-(6-
`carbomethoxyphenylsulfonyl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(2-pyridylmethyl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(3-pyridylmethyl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(4-pyridylmethyl)piperidin-4-yl)
`cycloheptylurea;
`N-(3 -amidinophenyl)-N' -(phenyl-N" -methylsulfamido)
`piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-((4-phenylsulfonylthiophen-2-yl)
`sulfonyl)-piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(4-pyridylmethylsulfonyl)
`piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(thiophen-2-ylsulfonyl)piperidin-
`4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(4-fluorobenzylsulfonyl)piperidin-
`4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(2-pyridylsulfonyl)piperidin-4-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(2-trifluormethylphenylsulfonyl)
`piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(2-phenylisopropylsulfonyl)
`piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-((l-((phenyl)-1,1-dimethyl)
`methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(methyl((phenylmethane)
`carbamide)morpholin-3-yl))cycloheptylurea;
`N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)
`morpholin-3-yl))cycloheptylurea;
`N-(3-amidinophenyl)-N'-(methyl((phenylmethane)sulfonyl)
`morpholin-3-yl))cycloheptylurea;
`N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)-piperidin-3-
`yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)
`piperidin-3-yl)cycloheptylurea;
`N-(3-amidinophenyl)-N'-(4-(2-sulfonamidophenyl)phenyl)
`cycloheptylurea;
`N-(3-amidinophenyl)-N'-(5-(2-sulfonamido-phenyl)
`pyridin-2-yl)cycloheptylurea; and,
`N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)
`phenyl))cycloheptylurea;
`or stereoisomers or pharmaceutically acceptable salt forms
`thereof.
`[8] In another preferred embodiment, the present invention
`provides compounds wherein:
`n is 2; and,
`R2 and R2" are on adjacent carbon atoms and combine to
`form a benzene ring substituted with 0-2 R1° or a 5-6
`membered aromatic heterocycle containing 0-2 hetera-
`toms selected from the group consisting of N, 0, and S
`and substituted with 0-2 R10a
`[9] In another more preferred embodiment, the present
`invention provides novel compounds of formula II:
`
`15 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`or stereoisomers or pharmaceutically acceptable salt forms
`thereof, wherein;
`ring N contains 0-2 N atoms and is substituted with 0-2
`R10; and,
`D is selected from CN, C(=NR11)NR12R13 NHC
`(=NR11)NR12R13 NR12CH(=NR" ), C(0)NR12R13
`and (CH2),NR12R13
`20 [10] In another even more preferred embodiment, the
`present invention provides compounds of formula II
`wherein:
`D is C(=NH)NH2;
`R1 is selected from H, (CH2),OR3, halo, (CH2),NR4R4',
`(CH2)rCO2H, (CH2)rC(=O)R4, (CH2),NR4C(=O)R4,
`(CH2),SO2R5, and (CH2),NHSO2R5;
`R4 and R4' are independently selected from H, OR3, C1_4
`alkyl, and NR3R3';
`R5 is selected from C1_4 alkyl and NR3R3';
`Z is selected from a bond, C1_4 alkylene, (CH2),C(0)
`(CH2)„ (CH2),C(0)NR3(CH2)„ (CH2)2NR3C(0)
`(CH2)„ (CH2)2OC(0)NR3(CH2)„ (CH2)2NR3C(0)O
`(CH2)„ (CH2)2NR3C(0)NR3(CH2)„ (CH2),S(0)p
`(CH2)„ and (CH2),SO2NR3(CH2)r; and,
`X is selected from C1_4 alkylene, —C(0)—, —C(0)
`CR3R3'—, —CR3R3'C(0)—, —C(0)O—, —C(0)
`OCR3R3'—, —CR3R3'C(0)O—, —OC(0)—, —OC
`(0)CR3R3'—, —CR3R3'OC(0)—, —S(0)--, —S(0)
`PCR3R3 — —CR3R3'S(0)P—, —C(0)NR3—,
`—NR3C(0)--, —NR3C(0)O—, —OC(0)NR3—,
`—NR3C(0)NR3—, —NR3— —NR3CR3R3'—,
`—CR3R3'NR3—, 0, —CR3R3'O—, and —OCR3R3'—.
`[11] In another further preferred embodiment, the present
`45 invention provides compounds of formula II, wherein:
`Z is selected from a bond, C14 alkylene, C(0)NR3(CH2)„
`S(0)2, S(0)2CH2, and (CH2),SO2NR3(CH2),;
`A is selected from phenyl substituted with 0-1 R6 and 6
`membered heterocyclic system containing 1 N and
`substituted with 0-1 R6; and,
`X is selected from C1_4 alkylene, —C(0)—, —C(0)
`CR3R3', —CR3R3'C(0)— —S(0)P—, —S(0)
`PCR3R3'—, —C(0)NR3—, and, —NR3—.
`[12] In another even further preferred embodiment, the
`55 present invention provides compounds selected from:
`1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-
`4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;
`1,2,4,5-tetrahydro-2-(thiopen-2-yl)-sulfonyl)piperidin-4-
`yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;
`60 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-
`4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-
`benzodiazepin-3-one; and,
`1,2,4,5-tetrahydro-2-(thiophen-2-yl)-sulfonyl)piperidin-4-
`yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-
`65 benzodiazepin-3-one.
`In a second embodiment, the present invention provides
`novel pharmaceutical compositions, comprising: a pharma-
`
`35 (cid:9)
`
`40 (cid:9)
`
`5o (cid:9)
`
`(cid:9)
`

`
`5,925,635
`
`11
`ceutically acceptable carrier and a therapeutically effective
`amount of a compound of formula (I) or a pharmaceutically
`acceptable salt or prodrug form thereof.
`In a third embodiment, the present invention provides a
`novel method for treating or preventing a thromboembolic
`disorder, comprising: administering to a patient in need
`thereof a therapeutically effective amount of a compound of
`formula (I) or a pharmaceutically acceptable salt or prodrug
`form thereof.
`
`DEFINITIONS
`The compounds herein described may have asymmetric
`centers. Compounds of the present invention containing an
`asymmetrically substituted atom may be isolated in optically
`active or racemic forms. It is well known in the art how to
`prepare optically active forms, such as by resolution of
`racemic forms or by synthesis from optically active starting
`materials. Many geometric isomers of olefins, C=N double
`bonds, and the like can also be present in the compounds
`described herein, and all such stable isomers are contem-
`plated in the present invention. Cis and trans geometric
`isomers of the compounds of the present invention are
`described and may be isolated as a mixture of isomers or as
`separated isomeric forms. All chiral, diastereomeric, race-
`mic forms and all geometric isomeric forms of a structure
`are intended, unless the specific stereochemistry or isomeric
`form is specifically indicated.
`The term "substituted," as used herein, means that any
`one or more hydrogens on the designated atom is replaced
`with a selection from the indicated group, provided that the
`designated atom's normal valency is not exceeded, and that
`the substitution results in a stable compound. When a
`substitent is keto (i.e., =O), then 2 hydrogens on the atom
`are replaced.
`When any variable (e.g., R6) occurs more than one time
`in any constituent or formula for a compound, its definition
`at each occurrence is independent of its definition at every
`other occurrence. Thus, for example, if a group is shown to
`be substituted with 0-2 R6, then said group may optionally
`be substituted with up to two R6 groups and R6 at each
`occurrence is selected independently from the definition of
`R6. Also, combinations of substituents and/or variables are
`permissible only if such combinations result in stable com-
`pounds.
`When a bond to a substituent is shown to cross a bond
`connecting two atoms in a ring, then such substituent may be
`bonded to any atom on the ring. When a substituent is listed
`without indicating the atom via which such substituent is
`bonded to the rest of the compound of a given formula, then
`such substituent may be bonded via any atom in such
`substituent. Combinations of substituents and/or variables
`are permissible only if such combinations result in stable
`compounds.
`As used herein, "C1_6 alkyl" is intended to include both
`branched and straight-chain saturated aliphatic hydrocarbon
`groups having the specified number of carbon atoms,
`examples of which include, but are not limited to, methyl,
`ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,
`pentyl, and hexyl; "Alkenyl" is intended to include hydro-
`carbon chains of either a straight or branched configuration
`and one or more unsaturated carbon-carbon bonds which
`may occur in any stable point along the chain, such as
`ethenyl, propenyl, and the like.
`"Halo" or "halogen" as used herein refers to fluoro,
`chloro, bromo, and iodo; and "counterion" is used to rep-
`resent a small, negatively charged species such as chloride,
`bromide, hydroxide, acetate, sulfate, and the like.
`
`12
`As used herein, "carbocycle" or "carbocyclic residue" is
`intended to mean any stable 3- to 7-membered monocyclic
`or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of
`which may be saturated, partially unsaturated, or aromatic.
`5 Examples of such carbocycles include, but are not limited to,
`cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane,
`[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
`[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,
`10 adamantyl, or tetrahydronaphthyl (tetralin).
`As used herein, the term "heterocycle" or "heterocyclic
`system" is intended to mean a stable 5- to 7-membered
`monocyclic or bicyclic or 7- to 10-membered bicyclic
`heterocyclic ring which is saturated partially unsaturated or
`1s unsaturated (aromatic), and which consists of carbon atoms
`and from 1 to 4 heteroatoms independently selected from the
`group consisting of N, 0 and S and including any bicyclic
`group in which any of the above-defined heterocyclic rings
`is fused to a benzene ring. The nitrogen and sulfur heteroa-
`20 toms may optionally be oxidized. The heterocyclic ring may
`be attached to its pendant group at any heteroatom or carbon
`atom which results in a stable structure. The heterocyclic
`rings described herein may be substituted on carbon or on a
`nitrogen atom if the resulting compound is stable. If spe-
`25 cifically noted, a nitrogen in the heterocycle may optionally
`be quaternized. It is preferred that when the total number of
`S and 0 atoms in the heterocycle exceeds 1, then these
`heteroatoms are not adjacent to one another. As used herein,
`the term "aromatic heterocyclic system" is intended to mean
`30 a stable 5- to 7-membered monocyclic or bicyclic or 7- to
`10-membered bicyclic heterocyclic aromatic ring which
`consists of carbon atoms and from 1 to 4 heterotams
`independently selected from the group consisting of N, 0
`and S. It is preferred that the total number of S and 0 atoms
`35 in the heterocycle is not more than 1.
`Examples of heterocycles include, but are not limited to,
`1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,
`2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole,
`4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,
`4o benzimidazolyl, benzofuranyl, benzothiofuranyl,
`benzothiophenyl, benzoxazolyl, benzthiazolyl,
`benztriazolyl, benztetrazolyl, benzisoxazolyl,
`benzisothiazolyl, benzimidazalonyl, benzothiadiazolyl,
`carbazolyl, 4aH-carbazolyl, (3-carbolinyl, chromanyl,
`45 chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-
`dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,
`furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
`1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
`isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
`so isoindolyl, isoquinolinyl(benzimidazoly