HIV INHIBITING BICYCLIC PYRIMIDINE DERIVATIVES

Abstract

HIV replication inhibitors of formula

##STR00001##

N-oxides, pharmaceutically acceptable addition salts, quaternary amines or stereoisomeric forms thereof, wherein -a.sup.1=a.sup.2-a.sup.3=a.sup.4- is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; -b.sup.1=b.sup.2-b.sup.3=b.sup.4- is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; n and m is 0, 1, 2, 3 and in certain cases also 4; R.sup.1 is hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; optionally substituted C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; R.sup.2 is OH; halo; optionally substituted C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; substituted amino; polyhalomethyl; polyhalomethylthio; —S(═O).sub.pR.sup.6; C(═NH)R.sup.6; R.sup.2a is CN; amino; substituted amino; optionally substituted C.sub.1-6alkyl; halo; optionally substituted C.sub.1-6alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R.sup.16; optionally substituted C.sub.1-6alkyloxyC.sub.1-6alkyl; substituted C.sub.2-6alkenyl or C.sub.2-6alkynyl; —C(═N—O—R.sup.8)—C.sub.1-4alkyl; R.sup.7 or X—R.sup.7; R.sup.3 is CN; amino; C.sub.1-6alkyl; halo; optionally substituted C.sub.1-6alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R.sup.16; substituted C.sub.1-6alkyl; optionally substituted C.sub.1-6alkyloxyC.sub.1-6alkyl; substituted C.sub.2-6alkenyl or C.sub.2-6alkynyl; —C(═N—O—R.sup.8)—C.sub.1-4alkyl; R.sup.7; —X—R.sup.7; R.sup.4 is halo; OH; optionally substituted C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl; C.sub.3-7cycloalkyl; C.sub.1-6alkyloxy; CN; nitro; polyhaloC.sub.1-6alkyl; polyhaloC.sub.1-6alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C.sub.1-4alkyl)amino or R.sup.7; -A-B— is —CR.sup.5═N—, —N═N—, —CH.sub.2—CH.sub.2—, —CS—NH—, —CO—NH—, —CH═CH—;
pharmaceutical compositions comprising these; methods for the preparation of these compounds and compositions; the use of these compounds for the prevention or the treatment of HIV infection.

Claims

1-21. (canceled)

22. A compound of formula ##STR00059## a N-oxide; a pharmaceutically acceptable addition salt; a quaternary amine; or a stereochemically isomeric form thereof, wherein -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of a formula selected from the group consisting of:
—CH═CH—CH═CH—  (a-1);
—N═CH—CH═CH—  (a-2);
—N═CH—N═CH—  (a-3);
—N═CH—CH═N—  (a-4); and
—N═N—CH═CH—  (a-5); -b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents a bivalent radical of a formula selected from the group consisting of:
—CH═CH—CH═CH—  (b-1);
—N═CH—CH═CH—  (b-2);
—N═CH—N═CH—  (b-3);
—N═CH—CH═N—  (b-4); and
—N═N—CH═CH—  (b-5); n is 0, 1, 2, 3 and in case -a.sup.1=a.sup.2-a.sup.3=a.sup.4- is (a-1), then n may also be 4; m is 0, 1, 2, 3 and in case -b.sup.1=b.sup.2-b.sup.3═b.sup.4- is (b-1), then m may also be 4; -A-B— represents a bivalent radical of a formula: —CS—NH—; R.sup.1 is a member selected from the group consisting of: hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; and C.sub.1-6alkyl substituted with a member selected from the group consisting of: formyl, C.sub.1-6alkylcarbonyl, and C.sub.1-6alkyloxycarbonyl; each R.sup.2 independently is selected from the group consisting of: hydroxy; halo; C.sub.1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R.sup.6; C.sub.3-7cycloalkyl; C.sub.2-6alkenyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R.sup.6; C.sub.2-6alkynyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R.sup.6; C.sub.1-6alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or di(C.sub.1-6alkyl)amino; polyhalomethyl; polyhalomethylthio; —S(═O).sub.pR.sup.6; —NH—S(═O).sub.pR.sup.6; —C(═O)R.sup.6;—NHC(═O)H; —C(═O)NHNH.sub.2; NHC(═O)R.sup.6; and C(═NH)R.sup.6; R.sup.2a is a member selected from the group consisting of: cyano; aminocarbonyl; amino; C.sub.1-6alkyl; halo; C.sub.1-6alkyloxy wherein the C.sub.1-6alkyl moiety of the C.sub.1-6alkyloxy may optionally be substituted with cyano; NHR.sup.13; NR.sup.13R.sup.14; —C(═O)—NHR.sup.13; —C(═O)—NR.sup.13R.sup.14; C(═O)—R.sup.15; —CH═N—NH—C(═O)—R.sup.16; C.sub.1-6alkyl substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.1-6alkyl substituted with hydroxy and a second substituent selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.1-6alkyloxyC.sub.1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.2-6alkenyl substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.2-6alkynyl substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; —C(═N—O—R.sup.8)—C.sub.1-4 alkyl; R.sup.7; and —X—R.sup.7; R.sup.3 is a member selected from the group consisting of: cyano; aminocarbonyl; amino; C.sub.1-6alkyl; halo; C.sub.1-6alkyloxy wherein the C.sub.1-6alkyl moiety of the C.sub.1-6alkyloxy may optionally be substituted with cyano; NHR.sub.13; NR.sup.13R.sup.14; —C(═O)—NHR.sup.13; —C(═O)—NR.sup.13R.sup.14; —C(═O)—R.sup.15; —CH═N—NH—C(═O)‥R.sup.16; C.sub.1-6alkyl substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.1-6alkyl substituted with hydroxy and a second substituent selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.1-6alkyloxyC.sub.1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.2-6alkenyl substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; C.sub.2-6alkynyl substituted with one, two or three substituents each independently selected from halo, cyano, NR.sup.9R.sup.10, —C(═O)—NR.sup.9R.sup.10, —C(═O)—C.sub.1-6alkyl and R.sup.7; —C(═N—O—R.sup.8)—C.sub.1-4alkyl; R.sup.7; and —X—R.sup.7; X is a member selected from the group consisting of: —NR.sup.1—, —O—, —C(═O)—, —S—, and —S(═O).sub.p—; each R.sup.4 independently is a member selected from the group consisting of: halo; hydroxy; C.sub.1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R.sup.6; C.sub.2-6alkenyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R.sup.6; C.sub.2-6alkynyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R.sup.6; C.sub.3-7cycloalkyl; C.sub.1-6alkyloxy; cyano; nitro; polyhaloC.sub.1-6alkyl; polyhaloC.sub.1-6alkyloxy; aminocarbonyl; mono- or di(C.sub.1-4 alkyl)amino-carbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylcarbonyl; formyl; amino; mono- or di(C.sub.1-4 alkyl)amino; and R.sup.7; Q is a member selected from the group consisting of: hydrogen, C.sub.1-6alkyl, halo, polyhaloC.sub.1-6alkyl, and —NR.sup.9R.sup.10; R.sup.6 is a member selected from the group consisting of: C.sub.1-4 alkyl, amino, mono- or di(C.sub.1-4alkyl)amino, and polyhaloC.sub.1-4alkyl; R.sup.7 is a member selected from the group consisting of: a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle; or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle; wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxy C.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono and di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, formyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, —CH(═N—O—R.sup.8), R.sup.7a,—X—R.sup.7a and R.sup.7a—C.sub.1-.sub.4alkyl; R.sup.7a is a member selected from the group consisting of: a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle; or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle; wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)amino C.sub.1-6alkyl, formyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R.sup.8); R.sup.8 is a member selected from the group consisting of: hydrogen, C.sub.1-4alkyl, aryl or arylC.sub.1-4alkyl; R.sup.9 and R.sup.10 each independently are a member selected from the group consisting of: hydrogen; hydroxy; C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino; mono- or di(C.sub.1-6alkyl)aminocarbonyl; —CH(═NR.sup.11) and R.sup.7 wherein each of the aforementioned C.sub.1-6alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from the group consisting of: hydroxy, C.sub.1-6alkyloxy, hydroxyC.sub.1-4alkyloxy, carboxyl, C.sub.1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C.sub.1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O).sub.pR.sup.6, —NH—S(═O).sub.pR.sup.6, —C(═O)R.sup.6, —NHC(═O)H, —C(═O)NHNH.sub.2, —NHC(═O)R.sup.6, —C(═NH)R.sup.6, and R.sup.7; or R.sup.9 and R.sup.10 may be taken together to form a bivalent or trivalent radical of a formula selected from the group consisting of:
—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—  (d-1);
—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—  (d-2);
—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—  (d-3);
—CH.sub.2—CH.sub.2—S—CH.sub.2—CH.sub.2—  (d-4);
—CH.sub.2—CH.sub.2—NR.sup.12—CH.sub.2—CH.sub.2—  (d-5);
—CH.sub.2—CH═CH—CH.sub.2—  (d-6); and
═CH—CH═CH—CH═CH—  (d-7); RH is a member selected from the group consisting of: cyano; C.sub.1-4alkyl optionally substituted with C.sub.1-4 alkyloxy, cyano, amino, mono- or di(C.sub.1-4alkyl)amino or aminocarbonyl; C.sub.1-4alkylcarbonyl; C.sub.1-4 alkyloxycarbonyl; aminocarbonyl; and mono- or di(C.sub.1-4alkyl)aminocarbonyl; R.sup.12 is hydrogen or C.sub.1-4 alkyl; R.sup.13 and R.sup.14 each independently are a member selected from the group consisting of: C.sub.1-6alkyl optionally substituted with cyano or aminocarbonyl; C.sub.2-6alkenyl optionally substituted with cyano or aminocarbonyl; and C.sub.2-6alkynyl optionally substituted with cyano or aminocarbonyl; R.sup.15 is C.sub.1-6alkyl substituted with cyano or aminocarbonyl; R.sup.16 is C.sub.1-6alkyl optionally substituted with cyano, aminocarbonyl, or R.sup.7; each p is 1 or 2; each aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, C.sub.1-6alkyl-carbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, a radical Het and —X-Het; and Het is a member selected from the group consisting of: pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl quinolinyl, benzothienyl, and benzofuranyl; wherein each of the aforementioned Het may optionally be substituted with one or two C.sub.1-4 alkyl radicals.

23. A compound according to claim 22, wherein -a.sup.1=a.sup.2-a.sup.3≦a.sup.4- represents a bivalent radical of formula —CH═CH—CH═CH— (a-1); -b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents a bivalent radical of formula —CH═CH—CH═CH— (b-1); n is 0, 1 or 2; m is 0, 1 or 2; and R.sup.1 is a member selected from the group consisting of: hydrogen; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; and C.sub.1-6alkyloxycarbonyl.

24. A compound according to claim 22, wherein the compound has the formula ##STR00060## wherein R.sup.1, R.sup.2, R.sup.2a; R.sup.3, R.sup.4, -A-B—, m, n and Q are as defined in claim 1.

25. A compound according claim 22, wherein the compound has the formula ##STR00061## wherein R.sup.1, R.sup.2a; R.sup.3, R.sup.4, -A-B— and Q are as defined in claim 1.

26. A compound according to claim 22, wherein R.sup.2 is a member selected from the group consisting of: hydroxy; halo; C.sub.1-6alkyl optionally substituted with one substituent selected from halo, cyano and —C(═O)R.sup.6; C.sub.2-6alkenyl optionally substituted with one substituent selected from halo, cyano or —C(═O)R.sup.6; C.sub.2-6alkynyl optionally substituted with one substituent selected from halo, cyano or —C(═O)R.sup.6; C.sub.1-6alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or di(C.sub.1-6alkyl)-amino; and trifluoromethyl; R.sup.2a is a member selected from the group consisting of: cyano; aminocarbonyl; amino; C.sub.1-6alkyl; halo; C.sub.1-6alkyloxy wherein the C.sub.1-6alkyl moiety of the C.sub.1-6alkyloxy may optionally be substituted with cyano; NHR.sup.13; NR.sup.13R.sup.14; —C(═O)—NHR.sup.13; —C(═O)—NR.sup.13R.sup.14; —C(═O)—R.sup.15; —CH═N-NH—C(═O)—R.sup.16; C.sub.1-6alkyl substituted with one substituent selected from halo, cyano, —C(═O)—NR.sup.9R.sup.10, and —C(═O)—C.sub.1-6alkyl; C.sub.1-6alkyl substituted with hydroxy and a second substituent selected from halo, cyano, —C(═O)—NR.sup.9R.sup.10, and —C(═O)—C.sub.1-6alkyl; C.sub.1-6alkyloxyC.sub.1-6alkyl optionally substituted with one substituent selected from halo, cyano, —C(═O)—NR.sup.9R.sup.10, and —C(═O)—C.sub.1-6alkyl; C.sub.2-6alkenyl substituted with one substituent selected from halo, cyano, —C(═O)—NR.sup.9R.sup.10, and —C(═O)—C.sub.1-6alkyl; and C.sub.2-6alkynyl substituted with one substituent selected from halo, cyano, —C(═O)—NR.sup.9R.sup.10, and —C(═O)—C.sub.1-6alkyl; R.sup.3 is a member selected from the group consisting of: cyano; aminocarbonyl; amino; C.sub.1-6alkyl; halo; C.sub.1-6alkyloxy wherein C.sub.1-6alkyl may optionally be substituted with cyano; NHR.sup.13; NR.sup.13R.sup.14; —C(═O)—NHR.sup.13; —C(═O)—NR.sup.13R.sup.14; —C(═O)—R.sup.15; —CH═N—NH—C(═O)—R.sup.16; C.sub.1-6alkyl substituted with one substituent selected from halo, cyano, and —C(═O)—NR.sup.9R.sup.10; C.sub.1-6alkyl substituted with hydroxy and a second substituent selected from halo, cyano, and —C(═O)—NR.sup.9R.sup.10; C.sub.1-6alkyloxyC.sub.1-6alkyl optionally substituted with one substituent selected from halo, cyano, and—C(═O)—NR.sup.9R.sup.10; C.sub.2-6alkenyl substituted with one substituent selected from halo, cyano, and—C(═O)—NR.sup.9R.sup.10; and C.sub.2-6alkynyl substituted with one substituent selected from halo, cyano, and —C(═O)—NR.sup.9R.sup.10; and R.sup.4 is a member selected from the group consisting of: halo; hydroxy; C.sub.1-6alkyl optionally substituted with one substituent selected from halo, cyano and —C(═O)R.sup.6; C.sub.2-6alkenyl optionally substituted with one substituent selected from halo, cyano and —C(═O)R.sup.6; C.sub.2-6alkynyl optionally substituted with one substituent selected from halo, cyano and —C(═O)R.sup.6; C.sub.3-7cycloalkyl; C.sub.1-6alkyloxy; cyano; nitro; polyhaloC.sub.1-6alkyl; polyhaloC.sub.1-6alkyloxy; aminocarbonyl; mono- or di(C.sub.1-4 alkyl)aminocarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylcarbonyl; formyl; amino; mono- or di(C.sub.1-4 alkyl)amino and R.sup.7.

27. A compound according to claim 22, wherein R.sup.1 is hydrogen.

28. A compound according to claim 22, wherein R.sup.2 is halo; cyano; aminocarbonyl; alkyloxycarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyl substituted with cyano; or C.sub.2-6alkenyl substituted with cyano; R.sup.2a is halo; cyano; aminocarbonyl; C.sub.1-6alkyl substituted with cyano or aminocarbonyl; or C.sub.2-6alkenyl substituted with cyano or aminocarbonyl; R.sup.3 is halo; cyano; aminocarbonyl; C.sub.1-6alkyl substituted with cyano or aminocarbonyl; or C.sub.2-6alkenyl substituted with cyano or aminocarbonyl; R.sup.4 is halo; hydroxy; C.sub.1-6alkyl optionally substituted with cyano; C.sub.2-6alkenyl optionally substituted with cyano; C.sub.2-6alkynyl optionally substituted with cyano; C.sub.1-6alkyloxy; cyano; nitro; trifluoromethyl; aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkyloxycar bonyl; C.sub.1-6alkylcarbonyl; formyl; amino; or mono- or di(C.sub.1-4 alkyl)amino; and Q is hydrogen, amino, mono- or di—C.sub.1-4 alkylamino.

29. A compound according to claim 22 wherein n is 0; m is 2; R.sup.2 is halo, cyano, aminocarbonyl, C.sub.1-4 alkyl substituted with cyano, or C.sub.2-4alkenyl substituted with cyano; R.sup.2a is cyano, aminocarbonyl, C.sub.1-6alkyl substituted with cyano, or C.sub.2-6alkenyl substituted with cyano; R.sup.3 is cyano, C.sub.1-4alkyl substituted with cyano, or C.sub.2-4alkenyl substituted with cyano; R.sup.4 is halo, hydroxy, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkyloxy, cyano, nitro, or amino; and Q is hydrogen.

30. A compound according to claim 22 wherein R.sup.2 is cyano, or aminocarbonyl; R.sup.2a is cyano, aminocarbonyl, C.sub.1-4 alkyl substituted with cyano, or C.sub.2-4alkenyl substituted with cyano; R.sup.3 is C.sub.1-4 alkyl substituted with cyano, or C.sub.2-4alkenyl substituted with cyano; R.sup.4 is halo, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy; and Q is hydrogen.

31. A compound according to claim 22 wherein -A-B— is a radical of formula —CS—NH—; and R.sup.3 is C.sub.1-6alkyl substituted with cyano or aminocarbonyl; or C.sub.2-6alkenyl substituted with cyano or aminocarbonyl.

32. A compound according to claim 31, wherein R.sup.3 is C.sub.2-6alkyl substituted with cyano, or C.sub.2-6alkenyl substituted with cyano.

33. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in claim 22.

34. A process for preparing a pharmaceutical composition as claimed in claim 33, said process comprising mixing a compound as claimed in claim 1 with the carrier.

35. A compound selected from the group consisting of: ##STR00062## and an N-oxide; a pharmaceutically acceptable addition salt; a quaternary amine; or a stereochemically isomeric form thereof.

36. A composition comprising a therapeutically effective amount of ##STR00063## and an N-oxide; a pharmaceutically acceptable addition salt; a quaternary amine; or a stereochemically isomeric form thereof; and a pharmaceutically acceptable carrier.

37. A process for preparing a composition as claimed in claim 36, said process comprising mixing a compound selected from: ##STR00064## and an N-oxide; a pharmaceutically acceptable addition salt; a quaternary amine; or a stereochemically isomeric form thereof; with a carrier.

Description

EXAMPLES

Example 1

Synthesis of Intermediates B, C and D

[0315] ##STR00034##

Preparation of Intermediate B

[0316] A mixture of A (0.420 mol) in 2-methoxyethylether (diglyme, 250 ml) was stirred at 100° C. for 30 minutes. Then a mixture of cyanamide (0.630 mol) in water (30 ml) was added portion wise during 45 minutes. After stirring 24 h at 100° C., cyanamide (0.210 mol) was added. The mixture was stirred again at 100° C. for 48 h. The mixture was evaporated until dryness and the residue was crystallized from acetone. Yield: 70.5 g of intermediate B (85%, melting point:225° C.).

Preparation of Intermediate C

[0317] A mixture of B (0.356 mol) and 2-acetylbutyrolactone (1.068 mol) in ethanol (200 ml) and trietylamine (75 ml) was stirred at reflux for 48 h. The mixture was cooled and the precipitate was filtrated, then washed with ethanol and dried. Yield: 71 g of C (74%, melting point >250° C.).

Preparation of Intermediate D

[0318] A mixture of C (0.189 mol) and phosphorus oxychloride (200 ml) was stirred at 60° C. for 1 week. After cooling phosphorus oxychloride was evaporated. Water and K.sub.2CO.sub.3 10% was added and the mixture was extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. Yield: 45 g of D (78%, melting point:168° C.).

Example 2

Preparation of Intermediate E9 (4-bromo-2-chloro-6-fluoroaniline)

[0319] ##STR00035##

[0320] to N-chlorosuccinimide (0.199 mol) was added portionwise to a mixture of 4-bromo-2-fluoroaniline (0.158 mol) in acetonitrile (50 ml). The mixture was stirred at reflux for 2 hours, cooled and poured in a mixture of water and K2CO.sub.3 10%. The mixture was extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent : cyclohexane/ethyl acetate 80/20; 35-70 μm). The pure fractions were collected and the solvent evaporated. Yield: 31.6 g of 4-bromo-2-chloro-6-fluoroaniline, intermediate E9 (89%, melting point : <50° C.). Intermediate E9 was used to prepare intermediate F9 (see Table 1).

Example 3

Preparation of Intermediates F3, F4, F6

[0321] ##STR00036##

[0322] A mixture of 4-bromo-2-methylaniline (0.0268 mol), intermediate E3, palladium (0) acetate (0.00537 mol), tri-o-tolylphosphine (0.0268 mol) and acrylonitrile (0.0896 mol) in triethylamine (0.107 mol) and acetonitrile (70 ml) was stirred at 140° C. in a stainless-steel bomb for 18 h. After cooling, the mixture was filtered over celite and the filtrate was poured in water and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/Cyclohexane 50/50; 35-70 μm). The pure fractions were collected and the solvent evaporated. Yield: 3.2 g of intermediate F3 (75%, melting point : 105° C.)

Preparation of Intermediates F4 and F6

[0323] ##STR00037##

[0324] Intermediate F4 was prepared as described above for the preparation F3, using 4-bromo-2-ethylaniline as starting material. In a second step, N-bromosuccinimide (0.015 mol) was added portionwise to a mixture of 4-acrylonitrile-2-ethylaniline F4 (0.012 mol) in acetonitrile (25 ml). The mixture was stirred at room temperature overnight then poured in a mixture of water and K.sub.2CO.sub.3 10%. The mixture was extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: Cyclohexane/ethyl acetate 90/10; 15-40 μm). The pure fractions were collected and the solvent evaporated. Yield: 0.75 g of intermediate F6 (26%).

Example 4

Preparation of Intermediates H, I and J

[0325] ##STR00038##

Preparation of Intermediate H

[0326] A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0516 mol) and 4-(2-cyanoethenyl)-2,6-dimethylphenylamine (0.0516 mol) was stirred at 140° C. in an oil bath for 45 minutes, then poured in a mixture of water and K.sub.2CO.sub.3 10%. The precipitate was filtered and the filtrate extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2100; 35-70 μm). The pure fractions were collected and the solvent evaporated, yielding 6.0 g of intermediate H (35%, melting point: >250° C.).

Preparation of Intermediate I

[0327] A mixture of intermediate H (0.0182 mol) and 4-cyanoaniline (0.0182 mol) was heated at fusion for 5 minutes, then poured in a mixture of water and K.sub.2CO.sub.3 10%. CH.sub.2Cl.sub.2 and a small quantity of MeOH were added and the precipitate was filtered and dried, yielding 7.4 g of intermediate I (95%, melting point: >250° C.)

[0328] Preparation of Intermediate J

[0329] A mixture of intermediate I (0.0180 mol) and tin (II) chloride dihydrate (0.125 mol) in ethanol (100 ml) was stirred at 70° C. overnight, then poured in a mixture of water and K.sub.2CO.sub.3 10%. The precipitate was filtered over celite. The filtrate was removed and the precipitate was washed with CH.sub.2Cl2 and THF. The solvent was evaporated. Yield: 6.0 g of intermediate J (87%, melting point: >250° C.).

Example 5

Preparation of Intermediates K, L and M (6-chloro-2-fluorophenyl Analogs of Intermediates H, I and J).

[0330] A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0153 mol) and 4-(2-cyanoethenyl)-6-chloro-2-fluoro-phenylamine (0.0153 mol) was heated at fusion for 5 minutes, then poured in a mixture of water and K.sub.2CO.sub.3 10% and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2 100; 35-70 μm).

[0331] The pure fractions were collected and the solvent evaporated. Yield: 1.9 g of 2-chloro-4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidine, intermediate K (35%, melting point : 217° C.).

[0332] A mixture of intermediate K (0.000424 mol) and 4-cyanoaniline (0.000424 mol) was heated at fusion for 5 minutes, then poured in a mixture of water and K2CO.sub.3 10%. CH.sub.2Cl.sub.2 and a small quantity of MeOH was added and the precipitate was filtered and dried, yield : 1.34 g of 4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidinel]amino]benzonitrile, intermediate L (73%, melting point: >250° C.)

[0333] A mixture of intermediate L (0.00306 mol) and tin (II) chloride dihydrate (0.0214 mol) in ethanol (20 ml) was stirred at 70° C. overnight, then poured in a mixture of water and K.sub.2CO.sub.3 10%. The precipitate was filtered over celite. The filtrate was removed and the precipitate was washed with CH.sub.2Cl.sub.2 and THF. The solvent was evaporated. Yield: 1.1 g of 4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylaminol]-5-amino-pyrimidine]amino]benzonitrile, intermediate M (89%, melting point: >250° C.).

Example 6

Preparation of dihydro-pyrrolopyrimidine Compound 1

[0334] ##STR00039##

[0335] A mixture of F3 (0.00126 mol) and D (0.00126 mol) was stirred at 180° C. in an oil bath for 20 hours, then poured in a mixture of water and K.sub.2CO.sub.3 10% and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: MeOH/AcNH.sub.4/THF 40/40/20; Kromasil C18, 10 μm). The pure fractions were collected and the solvent evaporated. Yield : 0.18 g of compound 1 (E/Z:95/5) and 0.124 g of compound 1 (E/Z:65/35) (overall yield 61%, melting point (E/Z:95/5):244° C.).

Example 7

Preparation of dihydro-pyrrolopyrimidine Derivative 14

[0336] ##STR00040##

[0337] To a nitrogen flushed solution of 1(0.00051 mol) in MeOH (20 ml), palladium on activated carbon 10% Pd (0.2 g, 10% wt) was added. The mixture was stirred at room temperature under 3 bars of hydrogen for 20 hours, then filtered over celite and the solvent was evaporated. The residue was crystallized from CH.sub.2Cl.sub.2/diisopropyl-ethylether. Yield : 0.05 g of compound 14 (25%, melting point: 195° C.).

Example 8

Preparation of pyrrolopyrimidine Derivative 28

[0338] ##STR00041##

[0339] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.00222 mol) was added to a mixture of compound 11 (0.000738 mol), prepared following similar procedures as in example 1, in 1,4-dioxane (10 ml). The mixture was stirred at reflux for 2 hours, then cooled and poured on ice. The precipitate was filtered and purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 98/2/0.1 ; 10 μm). The pure fractions were collected and the solvent evaporated. The residue was crystallized from diisopropyl-ethylether. Yield: 0.022 g of compound 28 (7%, melting point: 217° C.).

Example 9

Preparation of pyrrolopyrimidine Derivative 34

[0340] ##STR00042##

Preparation of dihydro-pyrrolopyrimidine Compound 33

[0341] A mixture of ethyl 4-amino-3,5-dimethylbenzoate G (0.0155 mol) and D (0.0155 mol) was stirred at 180° C. in an oil bath for 20 hours, then poured in a mixture of water and K.sub.2CO.sub.3 10% and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chroma-tography over silica gel (eluent: CH.sub.2Cl.sub.2; 70-200 μm). The pure fractions were collected and the solvent evaporated. Yield : 2.2 g of compound 33 (33%, melting point : 92° C.).

Preparation of dihydro-pyrrolopyrimidine Derivative 33a

[0342] Compound 33 (0.00234 mol) was added portion wise to a mixture of lithium aluminum hydride (0.00702 mol) in THF (15 ml) at 0° C. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added, then water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was engaged in the next step with no further purification.

Preparation of dihydro-pyrrolopyrimidine Derivative 33b

[0343] To the residue of compound 33a (0.860 g) in CH.sub.2Cl.sub.2 was added manganese (IV) oxide (0.0104 mol) and the mixture was stirred at room temperature for 20 hours. After filtration over celite, the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2; 70-200 μm). The pure fractions were collected and the solvent evaporated. Yield: 0.160 g of compound 33b (18% for the two steps, melting point:oil).

Preparation of dihydro-pyrrolopyrimidine Compound 34

[0344] To a mixture of diethyl-(1-cyanoethyl)-phosphonate (0.000782 mol) in THF (5 ml) was added at 0° C. under nitrogen potassium tert-butoxide (0.000782 mol) and the mixture was stirred at room temperature for 1 hour. Compound 33b (0.000261 mol) was added and the mixture was stirred at room temperature for 20 hours, then poured in water and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:CH.sub.2C.sub.12 ; 35-70 μm). The pure fractions were collected and the solvent evaporated. The residue was crystallized from diisopropyl-ethylether. Yield: 0.075 g of compound 34 (E/Z:50/50) (68%, melting point:105° C.).

Example 10

Preparation of Compound 20

[0345] ##STR00043##

[0346] A mixture of J (0.000524 mol) and triethyl orthoformate (5 ml) was stirred at 100° C. for 20 hours. After cooling, water and K.sub.2CO.sub.3 10% was added. The precipitate was filtered off and dried. Yield: 0.155 g of compound 20 (76%, melting point >250° C.).

Example 11

Preparation of Compound 21

[0347] ##STR00044##

[0348] A mixture of J (0.000524 mol) and 2-furaldehyde (0.00524 mol) in nitrobenzene (5 ml) was stirred at 180° C. for 20 hours. After cooling, the residue was filtered over silica gel to eliminate nitrobenzene. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 99/1/0.1; 10 μm). The pure fractions were collected and the solvent evaporated. The residue was crystallized from diisopropyl-ethylether. Yield: 0.055 g of compound 21 (23%, melting point:236° C.).

Example 12

Preparation of Compound 29 (Triazolo Derivative)

[0349] ##STR00045##

[0350] Sodium nitrite (0.000629 mol) in water (2 ml) was slowly added at 0° C. to a mixture of J (0.000524 mol) in water (2.5 ml) and acetic acid (1.5 ml). The mixture was stirred at room temperature for 5 hours. The precipitate was filtered, washed with water and diisopropyl-ethylether and dried. Yield: 0.110 g of compound 29 (53%, melting point >250° C.).

Example 13

Preparation of Compound 30

[0351] ##STR00046##

[0352] The same procedure as in example 12 was used for the preparation of this derivative starting with 0.000370 mol of J analog and 0.000444 mol of sodium nitrite. Yield: 0.065 g of compound 30 (42%, melting point >250° C.).

Example 14

Preparation of Compound 31

[0353] ##STR00047##

[0354] Thiophosgene (0.000786 mol) was slowly added dropwise at 0° C. to a mixture of J (0.000524 mol) in 1,4-dioxane (5 ml). The mixture was stirred at room temperature for 4 hours and thiophosgene was added (0.000393 mol) and the mixture was stirred overnight. NH.sub.4OH was slowly added at 0° C. and the mixture was extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. Yield: 0.105 g of compound 31 (47%, melting point >250° C.)

Example 15

Preparation of Compound 32

[0355] ##STR00048##

[0356] The same procedure as in example 14 was used for the preparation of compound 32, starting with 0.000370 mol of intermediate M and 0.000554 mol of thiophosgene. Yield: 0.140 g of compound 32 (85%, melting point >250° C.).

Example 16

Preparation of Compound 26

[0357] ##STR00049##

[0358] Cyanogen bromide (0.000793 mol) was added portion wise at room temperature to intermediate J (0.000524 mol) in EtOH (6 ml) and THF (5 ml). The mixture was stirred at room temperature overnight. Cyanogen bromide (0.000264 mol) was added and the mixture was stirred at room temperature one day. The mixture was poured in a mixture of water and K.sub.2CO.sub.3 10% and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was crystallized from CH.sub.2Cl.sub.2. Yield : 0.092 g of 26 (43%, melting point: >250° C.).

[0359] Tables 1-6 list intermediates and compounds that were prepared according to one of the in above Examples (Ex. No.).

TABLE-US-00001 TABLE 1 [00050] Comp. Nr. Ex. No. R.sup.1 R.sup.2 Phys. Data F1 3 F F 168° C. F2 3 Et Et  69° C. F3 3 Me H 105° C. F4 3 Et H Oil F5 3 F H  99° C. F6 3 Et Br  75° C. F7 3 Me Br  87° C. F8 3 Cl Cl 131° C. F9 2 + 3 F Cl 144° C.  F10 3 OMe Me 110° C.

TABLE-US-00002 TABLE 2 [00051] Phys. Data and Comp. Nr. Ex. No. R.sup.4 R.sup.4a stereochemistry 1 6 Me H (E/Z:95/5); 244° C. 2 6 F F (E/Z:95/5); >250° C. 3 6 Et Et (E/Z:95/5); 139° C. 4 6 Et H (E); 210° C. 5 6 F H (E/Z:94/6); >250° C. 6 6 Et Br (E/Z:98/2); 146° C.  7a 6 Cl Cl (E/Z:97:3); 151° C.  7b 6 Cl Cl (E/Z:88/12) 8 6 OMe Me (E); >250° C. 9 6 Me Br (E/Z:85/15); 130° C. 10  6 F Cl (E); 138° C. 11  6 Me Me (E/Z:83/17); 215° C. 12  6 F F (Z); >250° C. 13  6 F Cl (Z); >250° C.

TABLE-US-00003 TABLE 3 [00052] Comp. Nr. Ex. No. R.sup.4 R.sup.4a Phys. Data 14 7 Me H 195° C. 15 7 Me Me 195° C. 16 7 Et Et 68-70° C.   17 7 Et H 176° C. 18 7 F H 189° C. 19 7 F F 191° C.

TABLE-US-00004 TABLE 4 [00053] Comp. Phys. Data and stereo- No. Ex. No. R.sup.4 R.sup.4a R.sup.5 chemistry 20 10 Me Me H (E); >250° C. 21 11 Me Me [00054] (E); 236° C. 22 11 Me Me ethyl (E); >250° C. 23 11 Me Me [00055] (E); >250° C. 24 11 F Cl H (E/Z:93/7); >250° C. 25 11 Me Me [00056] (E); 231° C. 26 16 Me Me NH.sub.2 (E); >250° C. 27 16 F Cl NH.sub.2 (E); >250° C.

TABLE-US-00005 TABLE 5 [00057] Ex. Phys. Data and Comp. Nr. No. A-B R.sup.4 R.sup.4a Q stereochemistry 28 8 —CH═CH— Me Me Me  217° C. 29 12 —N═N— Me Me H (E); >250° C. 30 13 —N═N— F Cl H (E); >250° C. 31 14 —C(═S)—NH— Me Me H (E/Z):98/2; >250° C. 32 15 —C(═S)—NH— F Cl H (E/Z):93/7; >250° C.

TABLE-US-00006 TABLE 6 [00058] Comp. Ex. Phys. Data and Nr. No. R.sup.3 stereochemistry 33 9 —COOEt 92° C. 34 9 —CH═C(CH.sub.3)CN (E/Z):50/50; 105° C.

Formulation Examples

[0360] Capsules

[0361] A compound of formula (I) is dissolved in organic solvent such as ethanol, methanol or methylene chloride, preferably, a mixture of ethanol and methylene chloride. Polymers such as polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA) or hydroxypropyl-methylcellulose (HPMC), typically 5 mPa.s, are dissolved in organic solvents such as ethanol, methanol methylene chloride. Suitably the polymer is dissolved in ethanol. The polymer and compound solutions are mixed and subsequently spray dried. The ratio of to compound/polymer is selected from 1/1 to 1/6. Intermediate ranges can be 1/1.5 and 1/3. A suitable ratio can be 1/6. The spray-dried powder, a solid dispersion, is subsequently filled in capsules for administration. The drug load in one capsule ranges between 50 and 100 mg depending on the capsule size used.

Film-Coated Tablets

[0362] Preparation of Tablet Core

[0363] A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.

[0364] Coating

[0365] To a solution of 10 g methylcellulose in 75 ml of denaturated ethanol there is added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then there is added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there is added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension and the whole is homogenized. The tablet cores are coated with the thus obtained mixture in a coating apparatus.

Antiviral Spectrum

[0366] Because of the increasing emergence of drug resistant HIV strains, the present compounds were tested for their potency against clinically isolated HIV strains harboring several mutations. These mutations are associated with resistance to reverse transcriptase inhibitors and result in viruses that show various degrees of phenotypic cross-resistance to the currently commercially available drugs such as for instance AZT and delavirdine.

[0367] The antiviral activity of the compound of the present invention has been evaluated in the presence of wild type HIV and HIV mutants bearing mutations at the reverse transcriptase gene. The activity of the compounds is evaluated using a cellular assay and the residual activity is expressed in pECso values. The columns IIIB and A-G in the table list the pEC50 values against various strains IIIB, A-G.

[0368] Strain IIIB is wild type HIV-LAI strain

[0369] Strain A contains mutation Y181C in HIV reverse transcriptase,

[0370] Strain B contains mutation K103N in HIV reverse transcriptase,

[0371] Strain C contains mutation L100I in HIV reverse transcriptase,

[0372] Strain D contains mutation Y188L in HIV reverse transcriptase,

[0373] Strain E contains mutations L100I and K103N in HIV reverse transcriptase,

[0374] Strain F contains mutations K103N and Y181C in HIV reverse transcriptase, and

[0375] Strain G contains mutations L100I, K103N, Y181C, V179I E138G L214F, V278V/I and A327A/V in HIV reverse transcriptase.

TABLE-US-00007 Comp. number IIIB A B C D E F G  1 8.4 7.9 9 8.9 7.7 7.8 7.1 5.5  2 9.1 7.9 9.2 9.3 8.4 9.1 7.4 5.7  3 7.9 7.8 8.5 8.7 7.8 8.5 7.7 5.7  4 8.4 8.3 9 9   7.9 8.1 7.6 5.1  5 7.7 6.3 7.9 7.8 6.6 6.9 — <4.6   6 8.3 7.7 8.3 8.4 7.5 8.3 7.5 5.5  7a 8.7 7.9 8.7 9.1 7.7 8.6 7.7 5.4  7b 9.1 8.1 9 9.1 7.7 8.5 7.7 5.4  8 8.5 7.6 8.4 8.3 7.5 7.6 7.2 4.9  9 8.9 8.3 8.4 8.7 8.4 7.8 7.7 <4.6  10 9.2 8.4 9.1 9.2 8 8.7 7.9 5.7 11 8.8 8.2 9 8.8 8.1 8.4 7.9 5.4 13 8.4 7.1 8.4 8.4 7 7.8 7   5.1 14 8.9 7.8 8.5 8.4 7 7.2 6.9 5.5 15 9 8.2 8.6 — 7.3 8 8   5.7 16 8.2 7.7 8.2 8.6 7 8.1 7.3 5.8 17 9 8.2 8.9 8.6 7.7 7.8 7.2 5.7 20 9.7 8.6 9.2 9.2 7.8 8.1 7.4 5.7 22 8.4 6.5 8.4 6.5 5.8 5.5 5.8 — 23 7.7 7.1 7.6 7.5 7.7 6.3 6.4 5.7 24 10 8.5 10 9.7 7.9 8.2 7.9 5.7 25 8.1 7.5 7.6 7.2 7.5 5.9 7.2 5.6 26 8.6 7.6 7.9 7.7 7.1 6.9 7.2 4.9 27 7.7 7.1 — 7.1 6.3 6.2 6.7 5.2 28 8.5 7.9 8.5 8.6 7.7 8.5 7.8 5.7 29 9.1 7.8 8.8 8.3 7.7 7.1 — 5.4 31 9 7.9 8.6 8.6 7.1 6.4 7.4 4.8 33 7.3 5.6 6.9 6.1 6.2 5.4 5.5 4.9 34 8.7 7.8 8.6 8.4 7.7 7.8 7.7 5.4