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HK1161092A - Pyrimidine derivatives for the prevention of hiv infection - Google Patents

Pyrimidine derivatives for the prevention of hiv infection Download PDF

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Publication number
HK1161092A
HK1161092A HK12101603.3A HK12101603A HK1161092A HK 1161092 A HK1161092 A HK 1161092A HK 12101603 A HK12101603 A HK 12101603A HK 1161092 A HK1161092 A HK 1161092A
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HK
Hong Kong
Prior art keywords
alkyl
group
cyano
substituted
amino
Prior art date
Application number
HK12101603.3A
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Chinese (zh)
Inventor
Heeres Jan
Joannes Lewi Paulus
René de Jonge Marc
Maria Henricus Koymans Lucien
Frans Desiré Daeyaert Frederik
Maarten Vinkers Hendrik
Adriaan Jan Janssen Paul
Emile Georges Guillemont Jérôme
Therese Jeanne Pasquier Elisabeth
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Janssen Pharmaceutica N.V.
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Publication of HK1161092A publication Critical patent/HK1161092A/en

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Description

Pyrimidine derivatives for the prevention of HIV infection
The present application is a divisional application of the following applications: application date: 2 month 4 day 2004; application No.: 200480003460.4(PCT/EP 2004/001011); the invention name is as follows: as above.
Technical Field
The present invention relates to pyrimidine derivatives for the prevention of HIV infection. The invention relates in particular to the use of pyrimidine derivatives for the preparation of a medicament for the prevention of HIV (human immunodeficiency virus) infections obtained by sexual intercourse and the associated intimate contact between partners, more in particular to the prevention of HIV infections obtained by vaginal intercourse.
Background
AIDS (acquired immune deficiency syndrome) is the fourth leading cause of death in the world and the first in africa. There is still no effective treatment and vaccine for AIDS.
Therefore, to be able to control the AIDS/HIV epidemic, it is of utmost importance to prevent the transmission of the HI virus.
Sexual transmission is a prevalent mode of transmission of HIV. Adherence to and proper use of condoms completely prevents the aforementioned sexual transmission of HIV. However, despite the enhanced preventive programs to increase condom use, condoms have not been systematically used, particularly in third world countries, which are serious areas of AIDS/HIV epidemic infection. Especially in developing countries, men do not accept condoms and do not like to use them, while women often lack the right to determine when, where and how intercourse is to be performed, and are therefore not generally in a position to determine mandatory use of condoms.
Therefore, the use of alternative condoms to prevent sexually transmitted infections, especially HIV, is of great importance.
An effective alternative to condoms is the topical application of a microbicide. A microbicide is a chemical entity that prevents or reduces the spread of sexually transmitted infections when applied to the site where the spread occurs.
Several classes of microbicides have been evaluated for their effect in preventing HIV transmission: products with detergent-surfactant like modes of action (e.g. nonoxynol-9), but which may cause damage to vaginal epithelial cells; an acid buffer; a lactic acid bacterium; negatively charged natural or synthetic products (e.g., sulfated polysaccharides) that interfere with HIV binding to target cells; an HIV proliferation inhibitor.
The present invention relates to the use of pyrimidine derivatives for the prevention of HIV infection, the prevention of transmission of HIV infection through sexual intercourse and related intimate contact between partners.
The pyrimidine compounds exhibit activity in inhibiting HIV replication in HIV-infected warm-blooded animals. Their enhanced role in inhibiting replication is particularly prominent in mutant strains, i.e., strains resistant to known drugs (single-resistant or multidrug-resistant HIV strains).
In addition to having HIV replication inhibiting activity in HIV-infected warm-blooded animals, the compounds of the present invention may also prevent HIV transmission in HIV-infected warm-blooded animals, especially humans infected with HIV through sexual intercourse and related intimate contact between partners. The compound has a preventive effect, so that the warm-blooded animal can be prevented from being infected; they can also provide protection after exposure, meaning that the compounds can still prevent HIV infection when used after sexual intercourse and sexual partner related intimate contact has taken place. Furthermore, the compounds have little or no immunosuppressive activity at therapeutically effective doses.
Compounds structurally related to the present compounds have been disclosed in the prior art.
WO 99/50250 and WO 00/27825 disclose substituted aminopyrimidines having HIV replication inhibiting properties.
WO 97/19065 discloses substituted 2-anilinopyrimidines as protein kinase inhibitors.
WO 00/62778 relates to cyclic protein tyrosine kinase inhibitors.
WO 98/41512 describes substituted 2-anilinopyrimidines as protein kinase inhibitors
US 5,691,364 describes benzamidine derivatives and their use as anticoagulants.
WO 00/78731 describes 5-cyano-2-aminopyrimidine derivatives as KDR kinase or FGFr kinase inhibitors for the prevention and treatment of angiogenesis-related diseases.
Disclosure of Invention
Thus, one aspect of the present invention relates to the use of said compounds for the preparation of a medicament for the prevention of HIV infection obtained by sexual intercourse or related intimate contact between partners, wherein the compounds, N-oxides, pharmaceutically acceptable addition salts, quaternary amines or stereochemically isomeric forms thereof have the formula
Wherein
-a1＝a2-a3＝a4-represents a divalent radical of formula
-CH＝CH-CH＝CH- (a-1)；
-N＝CH-CH＝CH- (a-2)；
-N＝CH-N＝CH- (a-3)；
-N＝CH-CH＝N- (a-4)；
-N＝N-CH＝CH- (a-5)；
-b1＝b2-b3＝b4-represents a divalent radical of formula
-CH＝CH-CH＝CH- (b-1)；
-N＝CH-CH＝CH- (b-2)；
-N＝CH-N＝CH- (b-3)；
-N＝CH-CH＝N- (b-4)；
-N＝N-CH＝CH- (b-5)；
n is 0, 1, 2, 3 or 4; and is in-a1＝a2-a3＝a4In case of-being (a-1), then n can also be 5;
m is 1, 2, 3, and in-b1＝b2-b3＝b4In the case of-being (b-1), m may also be 4;
R1is hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy substituted C1-6An alkyl group; quilt C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
each R2Independently is hydroxy, halo, optionally cyano or-C (═ O) R6Substituted C1-6Alkyl radical, C3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkynyl, C1-6Alkoxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino, polyhalomethyl, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6Or a group of the formula
Wherein each A1Independently N, CH or CR6(ii) a And
A2is NH, O, S or NR6；
X1is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、C1-4Alkanediyl, -CHOH-, -S (═ O)P-、-X2-C1-4alkanediyl-or-C1-4alkanediyl-X2-；
X2is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-CHOH-、-S-、-S(＝O)P-；
R3Is NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；
-CH＝N-NH-C(＝O)-R16(ii) a Is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein 2 hydrogen atoms bound to the same carbon atom are replaced by C1-4Alkanediyl substitution;
by hydroxy and a second group selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；
X3is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-S-、-S(＝O)P-、-X2-C1-4Alkanediyl-, -C1-4alkanediyl-X2a-、-C1-4alkanediyl-X2b-C1-4Alkanediyl, -C (═ N-OR)8)-C1-4Alkanediyl-;
wherein X2ais-NH-NH-, -N-, -O-, -C (O) -, -S (O)P-；
And the combination of (a) and (b),
X2bis-NH-NH-, -N-, -C (O) -, -S (O)P-；
R4Is halo, hydroxy, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy, cyano, nitro, polyhaloC1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyl, formyl, amino, mono-or di (C)1-4Alkyl) amino or R7；
R5Is hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl or C1-6Alkylcarbonyloxy substituted C1-6An alkyl group; quilt C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
R6is C1-4Alkyl, amino, mono-or di(C1-4Alkyl) amino or polyhaloC1-4An alkyl group;
R7is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents, each substituent being independently selected from halo, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8)、R7a、-X3-R7aOr R7a-C1-4An alkyl group;
R7ais a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring chain systems may optionally be substituted with one, two, three, four or five substituents, each substituent being independently selected from halo, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8)；
R8Is hydrogen, C1-4Alkyl, aryl or aryl C1-4An alkyl group;
R9and R10Each independently is hydrogen; a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein each of the above C1-6The alkyl groups may be optionally and independently substituted with one or two substituents each independently selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7(ii) a Or
R9And R10May be combined together to form a divalent or trivalent radical of the formula
-CH2-CH2-CH2-CH2- (d-1)
-CH2-CH2-CH2-CH2-CH2- (d-2)
-CH2-CH2-O-CH2-CH2- (d-3)
-CH2-CH2-S-CH2-CH2- (d-4)
-CH2-CH2-NR12-CH2-CH2- (d-5)
-CH2-CH＝CH-CH2- (d-6)
＝CH-CH＝CH-CH＝CH- (d-7)
R11Is cyano; optionally is covered with C1-4Alkoxy, cyano, amino,Mono-or di (C)1-4Alkyl) amino or aminocarbonyl substituted C1-4An alkyl group; c1-4An alkylcarbonyl group; c1-4An alkoxycarbonyl group; an aminocarbonyl group; mono-or di (C)1-4Alkyl) aminocarbonyl;
R12is hydrogen or C1-4An alkyl group;
R13and R14Each independently being C optionally substituted by cyano or aminocarbonyl1-6Alkyl, C optionally substituted by cyano or aminocarbonyl2-6Alkenyl, C optionally substituted by cyano or aminocarbonyl2-6An alkynyl group;
R15is C substituted by cyano or aminocarbonyl1-6An alkyl group;
R16is C optionally substituted by cyano or aminocarbonyl1-6Alkyl, or is R7；
p is 1 or 2;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents, each substituent being independently selected from halo, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, R7or-X3-R7。
C as a radical or part of a radical used hereinbefore or hereinafter1-4Alkyl is defined as a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; c as a radical or part of a radical1-6Alkyl is defined as a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, e.g. C1-4Alkyl groups and pentyl, hexyl, 2-methylbutyl, etc.; c as a radical or part of a radical2-6Alkyl is defined as a straight or branched chain saturated hydrocarbon group having 2 to 6 carbon atoms such as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl, and the like; c1-4Alkanediyl is defined as a straight or branched chain saturated divalent hydrocarbon group having 1 to 4 carbon atoms such as methylene, 1, 2-ethanediyl or 1, 2-ethylene, 1, 3-propanediyl or 1, 3-propylene, 1, 4-butanediyl or 1, 4-butylene, and the like; c3-7Cycloalkyl groups are typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; c2-6Alkenyl is defined as straight and branched chain hydrocarbon radicals containing one double bond having from 2 to 6 carbon atoms such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; c2-6Alkynyl is defined as straight and branched chain hydrocarbon radicals containing one triple bond having from 2 to 6 carbon atoms such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; monocyclic, bicyclic or tricyclic saturated carbocycle denotes a ring system consisting of 1, 2 or 3 rings, said ring system consisting of carbon atoms only and said ring system comprising only single chains; monocyclic, bicyclic or tricyclic partially saturated carbocycle denotes a ring system consisting of 1, 2 or 3 rings, said ring system consisting of carbon atoms only and said ring system comprising at least one double bond, with the proviso that the ring system is not an aromatic ring system; a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring denotes an aromatic ring system consisting of 1, 2 or 3 rings, which ring system consists exclusively of carbon atoms; the term aromatic is known to the person skilled in the art and refers to a (conjugated) system which is cyclically conjugated by 4n +2 electrons, i.e.having 6, 10, 14, etc. pi-electrons (Huckel's law); monocyclic, bicyclic or tricyclic saturated heterocyclic ring denotes a ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S, said ring system comprising only single bonds; monocyclic, bicyclic or tricyclic partially saturated heterocycle represents a ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S and comprising at least one double bond, with the proviso that the ring system is not an aromatic ring system; monocyclic, bicyclic or tricyclic aromatic heterocyclesAn aromatic ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S.
Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [4, 2, 0] octyl, cyclononyl, cyclodecyl, decahydronaphthyl, tetradecahydroanthracenyl and the like.
Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [4, 2, 0] octenyl, cyclononenyl, cyclodecenyl, octahydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2, 3,4, 4a, 9, 9a, 10-octahydro-anthracenyl and the like.
Specific examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are phenyl, naphthyl, anthracenyl.
Specific examples of monocyclic, bicyclic or tricyclic saturated heterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydroAzolyl, isothiazolidinyl, or isothiazolidinylOxazolidinyl group,Diazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dihydropyrazinylAlkyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl, and the like.
Specific examples of monocyclic, bicyclic or tricyclic saturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, 2, 3-dihydro-1, 4-benzodioxinyl, indolinyl and the like.
Specific examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are azetidinyl, oxetanyl, pyrrolyl, furanyl, thienyl, imidazolyl, thienyl,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,Oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolinyl, indolyl, isoindolyl, benzofuranylAzolyl, benzimidazolyl, indazolyl, benzisoxazoleAzolyl, benzisothiazolyl, benzpyrazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, benzopyranyl, pyrrolopyridinyl, thienopyridinyl, furopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, isoquinoxalinylAn azolopyridinyl group,Azolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isothiazolopyrazinylAn azolopyrazinyl group,Azolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidyl, thiazolopyrimidyl, isoisothiazolopyrimidylAzolopyrimidinyl,Oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoisothiazolopyridazinylAzolopyridazinyl group,Azolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl,Oxadiazolyl, thiadiazolyl, triazolopyridyl,Oxadiazolopyrazines, thiadiazolopyrazines, triazolopyrazines, thiadiazolopyrazines, thia,Oxadiazolyl, thiadiazolyl, triazolopyrimidinyl,Oxadiazolidiazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazoAzolyl, imidazothiazolyl, imidazoimidazolyl, isooxazolylAzolotriazinyl, isothiazolo-triazinyl, pyrazolo-triazinyl, pyrazolotriazinyl,azolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxatriazinyl,Oxadiazolyl-triazinyl, thiadiazolyl-triazinyl, triazolo-triazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinylOxazinyl (phenoxazinyl) and the like.
In the above usage, the term (═ O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, and two of said (═ O) forms a sulfonyl moiety when attached to a sulfur atom.
The substituents used, whether hereinbefore or hereinafter, may each be independently selected from the numerous definitions set out below, such as R9And R10By way of example, all possible combinations that are chemically possible and form chemically stable molecules should be taken into account.
The term halo refers to fluoro, chloro, bromo and iodo. As used hereinbefore and hereinafter polyhalomethyl as a group or part of a group is defined as mono-or polyhalosubstituted methyl, especially methyl substituted with one or more fluorine atoms, for exampleSuch as difluoromethyl or trifluoromethyl; polyhaloC as a group or part of a group1-4Alkyl or polyhalo C1-6Alkyl is defined as mono-or polyhalosubstituted C1-4Alkyl or C1-6Alkyl groups such as those defined in halomethyl, 1-difluoro-ethyl, and the like. If more than one halogen atom is attached to the polyhalomethyl, polyhaloC1-4Alkyl or polyhalo C1-6When on the alkyl group in the definition of alkyl, they may be the same or different halogen atoms.
R7Or R7aThe term heterocycle in the definition is meant to include all possible isomers of heterocycles, for example, pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl.
If not otherwise indicated, R7Or R7aThe carbocyclic or heterocyclic ring as defined in (a) may be attached to the remainder of the molecule of formula (I) at any suitable time via any ring carbon or heteroatom. Thus, for example, when the heterocycle is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, etc., or when the carbocycle is naphthyl, it can be 1-naphthyl, 2-naphthyl, etc.
When any variable (e.g. R) occurs more than once in any constituent7、X2) Each definition is independent of time.
The line drawn from the substituent into the ring system indicates that the bond may be attached to any suitable ring atom.
For therapeutic use, salts of the compounds of structural formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also be of value in the preparation and purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are within the scope of the invention.
The pharmaceutically acceptable addition salts mentioned above are intended to include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can be conveniently obtained by treating the base form with a suitable acid. Suitable acids may be, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, and the like), sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1, 2, 3-propanetriacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like. Conversely, the salt form can be converted to the free base form by treatment with a base.
The compounds of formula (I) containing an acidic proton may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with suitable inorganic and organic bases. Suitable base salt forms include, for example, the ammonium salts, the alkali and alkaline earth metal salts (e.g., lithium, sodium, potassium, magnesium, calcium salts, and the like), salts with organic bases (e.g., primary, secondary, and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, tetrabutylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidinane, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, isoquinoline, benzathine G, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, hydrabamine salts), and salts with amino acids (e.g., arginine, lysine, and the like). Conversely, the salt form can be converted to the free acid form by treatment with an acid.
The term addition salt also comprises the hydrates and solvent adduct forms which the compounds of formula (I) are able to form. Examples of such forms are hydrates, alcoholates and the like.
The term "quaternary amine" as used above is defined as a quaternary ammonium salt which can be formed by the reaction of a compound of formula (I) between the basic nitrogen of the compound of formula (I) and a suitable quaternizing agent, for example, an optionally substituted alkyl, aryl or arylalkyl halide such as methyl iodide, benzyl iodide. Other reactants having good leaving groups may also be used, such as alkyl triflates, alkyl mesylates and alkyl p-toluenesulfonates. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The selective counter ion may be introduced by using an ion exchange resin.
The N-oxide forms of the present compounds are intended to include compounds of formula (I) wherein one or more tertiary nitrogen atoms are oxidized to the so-called N-oxide.
The compounds of formula (I) may be converted to the corresponding N-oxide form according to methods known in the art for converting a trivalent nitrogen into its N-oxide form. In general, the N-oxidation is carried out by reacting the starting materials of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals (e.g., sodium peroxide, potassium peroxide); suitable organic peroxides may comprise peroxy acids (e.g. benzophenonepoxoic acid) or halo-substituted peroxy benzoic acids (e.g. 3-chloroperoxybenzoic acid), peroxy alkanoic acids (e.g. peroxyacetic acid), alkyl hydroperoxides (e.g. t-butyl hydroperoxide). Suitable solvents are, for example, water, lower alcohols (e.g. ethanol, etc.), hydrocarbons (e.g. toluene), ketones (e.g. 2-butanone), halogenated hydrocarbons (e.g. dichloromethane) and mixtures of these solvents.
It will be appreciated that some compounds of formula (I) and N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof may contain one or more chiral centres and exist as stereochemically isomeric forms.
The term "stereochemically isomeric forms" as used hereinbefore defines all the possible stereoisomeric forms of the compounds of formula (I) and the N-oxides, addition salts, quaternary amines or physiologically functional derivatives thereof. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure, as well as each individual isomeric form of formula (I) and the N-oxide, salt, solvate or quaternary amine thereof, which is substantially free of other isomers, i.e. contains less than 10%, preferably less than 5%, particularly preferably less than 2% and most preferably less than 1% of other isomers. Thus, for example, when a compound of formula (I) is designated as (E), it means that the compound is substantially free of the (Z) isomer.
In particular, the stereocenter may have the R-or S-configuration; the substituents of the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. The compounds surrounding the double bond may have a stereochemistry at the double bond of E (opposite (entgegen)) or Z (together (zusammen)). The above terms cis, trans, R, S, E and Z are well known to those skilled in the art.
Stereochemically isomeric forms of the compounds of formula (I) are expressly intended to be embraced within the scope of the present invention.
The absolute stereochemical configuration of some compounds of formula (I), their N-oxides, salts, solvates or quaternary amines and intermediates used in their preparation is not experimentally determined. In these examples, without further reference to the actual stereochemical configuration, the first isolated stereoisomeric form is designated "a" and the second isolated stereoisomeric form is designated "B". However, if "a" and "B" have an enantiomeric relationship, the "a" and "B" stereoisomeric forms may be clearly characterized, for example, by their optical activity. The absolute configuration of these compounds can be determined by one skilled in the art using methods known in the art, such as X-ray diffraction. In case "a" and "B" are stereoisomeric mixtures, they may be further separated without further reference to the actual stereochemical configuration, whereby the separated respective first fractions are named "a 1" and "B1" and the second fractions are named "a 2" and "B2".
Purified stereochemically isomeric forms of the present compounds and intermediates involved in the chemical synthesis thereof may be obtained by employing procedures known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatographic techniques such as countercurrent distribution, liquid chromatography, and the like. Enantiomers can be obtained from a racemic mixture by first converting said racemic mixture into a mixture of diastereomeric salts or compounds with a suitable resolving agent, such as a chiral acid; the mixture of diastereomeric salts or compounds is then physically separated by methods such as selective or fractional crystallization or chromatographic techniques such as liquid chromatography; finally, the separated diastereomeric salt or compound is converted into the corresponding enantiomer, for example by treatment with a base. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the reaction involved exhibits stereospecificity. Preferably, if a specific stereoisomer is desired, the compound is synthesized by stereospecific methods of preparation. These methods preferably employ enantiomerically pure starting materials.
Alternative methods of separating the enantiomeric forms of the compounds of formula (I) and intermediates include liquid chromatography, particularly liquid chromatography using a chiral stationary phase.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Although such forms are not specifically shown in the above formula, they are included within the scope of the present invention.
The term "compounds of formula (I)" as used hereinafter is meant to also include their N-oxide forms, their salts, their quaternary amines and stereochemically isomeric forms thereof. Of particular interest are those compounds of formula (I) which are stereochemically pure.
An important group of compounds are those in which-a1＝a2-a3＝a4-compounds of formula (I) representing a divalent group of formula-CH- (a-1).
A further important group of compounds are those of formula (I) having the formula
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric forms thereof, wherein
-a1＝a2-a3＝a4-、-b1＝b2-b3＝b4-、R1、R2、R3、R4M and X1As defined hereinabove;
n' is 0, 1, 2 or 3, and in-a1＝a2-a3＝a4In the case where-is (a-1), n' may also be 4;
R2' is halogeno, C1-6Alkyl, trihalomethyl, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group;
provided that R is2' located opposite to NR1And (4) partial alignment.
Another important group of compounds are those of formula (I) having the formula
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric forms thereof, wherein
-b1＝b2-b3＝b4-、R1、R2、R3、R4M and X1As defined hereinabove; n' is 0, 1, 2, 3 or 4;
R2' is halogeno, C1-6Alkyl, trihalomethyl, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group.
A further group of more important compounds are those of formula (I) having the formula
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric forms thereof, wherein
R1、R2、R3、R4And X1As defined hereinabove;
n' is 0, 1, 2, 3 or 4;
R2' is halogeno, C1-6Alkyl, trihalomethyl, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group.
Also particular compounds are compounds of formula (I), (I ') or (I'), wherein one or possibly more of the following applies:
a) m is 1, 2 or 3, particularly 2 or 3, more particularly 2, even more particularly m is 2, and the two R' s4The substituents being situated relative to X1The 2 and 6 positions (ortho) of the moiety;
b) m is 1, 2 or 3 and R3Is located opposite to X1Partial 4 bits (para);
c)X1is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-，C1-4Alkanediyl, -CHOH-, -S (═ O)P-、-X2-C1-4alkanediyl-or-C1-4alkanediyl-X2-；
d) Wherein applicable n' is 0;
e) wherein applicable n is 1 and said R2The substituents being situated relative to NR14 positions (para) of the bond;
f)R2is hydroxy, halo, optionally cyano or-C (═ O) R6Substituted C1-6Alkyl radical, C3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkynyl, C1-6Alkoxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino, polyhalomethyl, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6Or a group of the formula
Wherein each A1Independently N, CH or CR6And are and
A2is NH, O, S or NR6；
g)R2' is halogeno, C1-6Alkyl, trihalomethyl, cyano, C substituted by cyano or aminocarbonyl1-6An alkyl group;
h)R2is cyano, aminocarbonyl or C substituted by cyano or aminocarbonyl, especially by cyano1-6An alkyl group;
i)R2' is cyano, aminocarbonyl or C substituted by cyano or aminocarbonyl, especially by cyano1-6An alkyl group.
Preferred embodiments of the compounds of the present invention include those of formula (I), (I ') or (I'), wherein R3Is NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a C substituted by cyano or aminocarbonyl2-6An alkyl group; by NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein two hydrogen atoms bound to the same carbon atom are replaced by C1-4Alkanediyl substitution; by hydroxy and a second group selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C optionally substituted by a substituent of (3)1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；R9aRepresents a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein at R9aEach of the above C in the definition of1-6The alkyl groups may optionally and individually be substituted by one or two independently of one anotherSelected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s); r9aOr with R10Combine to form a divalent or trivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5), (d-6) or (d-7) as defined above.
A further important group of compounds are those of the formula (I), (I ') or (I'), wherein R3Is NHR13、NR13R14、-C(＝O)-NHR13、-C(＝O)-NR13R14、-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a By NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein two hydrogen atoms bound to the same carbon atom are replaced by C1-4Alkanediyl substitution; by hydroxy and a second group selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C optionally substituted by a substituent of (3)1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；R9aRepresents a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl, -CH (═ NR)11) Or R7Wherein at R9aEach of the above C defined in (1)1-6The alkyl groups may optionally and individually be selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s); r9aOr with R10Combine to form a divalent or trivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5), (d-6) or (d-7) as defined above.
A further important group of compounds are those of the formula (I), (I ') or (I'), wherein R3is-CH-N-NH-C (═ O) -R16(ii) a By NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein two hydrogen atoms bound to the same carbon atom are replaced by C1-4Alkanediyl substitution; by hydroxy and a second group selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C optionally substituted by a substituent of (3)1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7(ii) a And R is9aAs defined above.
Another important group of compounds are those of formula (I), (I ') or (I'), wherein R is3Is NHR13、NR13R14、-C(＝O)-R15By one or more radicals each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein two hydrogen atoms bound to the same carbon atom are replaced by C1-4Alkanediyl substitution; by hydroxy and a second group selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C optionally substituted by a substituent of (3)1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7。
Important compounds also include those of formula (I), (I ') or (I'), wherein R3Is by NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein two hydrogen atoms bound to the same carbon atom are replaced by C1-4Alkanediyl substitution; by hydroxy and a second group selected from cyano、NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C optionally substituted by a substituent of (3)1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；R9aAs defined above.
Important compounds also include those of the formula (I), (I ') or (I'), wherein R is3Is selected from one or more of cyano, NR9R10Or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10Or R7C substituted by a substituent of2-6An alkenyl group; c substituted by cyano1-6Alkoxy radical C1-6An alkyl group; by hydroxy and a second group selected from cyano or R7C substituted by a substituent of1-6An alkyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7。
Another important group of compounds are those in which R is3Is R7Of formula (I), (I ') or (I').
A further important group of compounds are those of the formula (I), (I ') or (I'), wherein R3Is C substituted by cyano1-6Alkyl, especially C, substituted by cyano2-6Alkyl, more particularly ethyl or propyl substituted by cyano; or C substituted by cyano2-6An alkenyl group. Preferably C substituted by cyano2-6An alkenyl group.
Another important group of compounds are those of formula (I), (I ') or (I'), wherein R is3Is substituted by cyano and R7Substituted C1-6Alkyl, or by cyano and R7Substituted C2-6An alkenyl group.
A further important group of compounds are those of the formula (I), (I ') or (I'), wherein R3Is by R7Substituted C1-6An alkyl group.
Another group of more important compounds are those of formula (I), (I ') or (I'), wherein R is3is-C (═ N-O-R)8)-C1-4An alkyl group.
Another important group of compounds are those of formula (I), (I ') or (I'), wherein R is3Is substituted by hydroxy and a second group selected from cyano or R7C substituted by a substituent of1-6An alkyl group.
Another important group of compounds are those of formula (I), (I ') or (I'), wherein R is2Or R2' is cyano or aminocarbonyl, and R1Is hydrogen.
A further important group of compounds are those of the formula (I), (I ') or (I'), wherein m is 2 or 3 and X1is-NR5-、-O-、-C(＝O)-、-CH2-、-CHOH-、-S-、-S(＝O)P-, especially where X1is-NR5-or-O-.
A further important group of compounds are those of the formula (I), (I ') or (I'), wherein one or more, preferably all, of the following limitations apply:
a) n is at least 1, in particular 1; or n' is 0;
b)R2or R2' is cyano;
c) m is 1, 2 or 3;
d)R4is C1-6Alkyl, especially methyl; a nitro group; an amino group; a halo group; c1-6Alkoxy or R7；
e)R3Is R7、NR13R14、-C(＝O)R15、-CH＝N-NH-C(＝O)R16、-C(＝O)NHR13、-C(＝O)NR13R14、-C(＝N-OR8)-C1-4Alkyl, C substituted by cyano1-6Alkyl, C substituted twice by cyano1-6Alkyl radical, by NR9R10Substituted C1-6Alkyl, C substituted by hydroxy and cyano1-6Alkyl, by hydroxy and R7Substituted C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, C substituted by cyano1-6Alkoxy radical C1-6Alkyl radical, by R7Substituted C2-6Alkenyl, C substituted by cyano2-6Alkenyl, C substituted twice by cyano2-6Alkenyl, by cyano and R7Substituted C2-6Alkenyl, by cyano and-C (═ O) -C1-6Alkyl substituted C2-6Alkenyl, C substituted by cyano and halo2-6Alkenyl, by-C (═ O) -NR9R10Substituted C2-6Alkenyl, C substituted by halo2-6Alkenyl, C substituted twice by halogen2-6Alkenyl or by NR9R10Substituted C2-6An alkenyl group;
f)X3is-C (═ O) -, -CH2-C (═ O) -OR-C (═ N-OR)8)-C1-4Alkanediyl-;
g)X1is NH or O;
h)R1is hydrogen or C1-4Alkyl radical。
Preferred compounds of formula (I), (I '), (I ") or (I'") are compounds 1, 25, 84, 133, 152, 179, 233, 239, 247, 248, 255 (see tables 1, 2 and 3), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof.
The compounds of formula (I) are disclosed in WO 2003/016306, the preparation of which is also described. Some intermediates and starting materials are known compounds and are commercially available or can be prepared according to methods known in the art, or some of the compounds of formula (I) or described intermediates can be prepared according to the methods described in WO 99/50250 and WO 00/27825.
The present invention also relates to a novel compound, namely 4- [ [4- [4- (2-cyanovinyl) -2, 6-dimethylphenoxy ] -2-pyrimidinyl ] amino ] benzonitrile (E) (compound 255); an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.
The novel compounds can be prepared as follows:
a) NaH (60%) (0.0233mol) was added to 4-hydroxy-3, 5-dimethylbenzaldehyde (0.0233mol) in bis (toluene) under a nitrogen streamIn a mixture of alkanes (35 ml). The mixture was stirred for 5 minutes. 1-methyl-2-pyrrolidone (35ml) was added. The mixture was stirred for 10 minutes. Adding 4- [ (4-chloro-2-pyrimidine) amino]Benzonitrile (0.0212 mol). The mixture was stirred at 155 ℃ for 12 hours, poured into water and extracted with dichloromethane. The organic layer was separated, washed several times with water, dried (magnesium sulfate), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: dichloromethane 100; 35-70 μm). The pure fractions were collected and the solvent was evaporated. Obtained from CH3Crystallized from CN/diisopropyl ether. The precipitate was filtered off and dried to yield 2.2g of intermediate 1.
b) Potassium tert-butoxide (0.0065mol) was added in portions at 5 ℃ under a stream of nitrogen gasDiethyl cyanomethylphosphonate (0.0065mol) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 1 hour. A solution of intermediate 1(0.0044mol) in tetrahydrofuran (20ml) was added and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane. The organic layer was separated, dried (magnesium sulfate), filtered and the solvent was evaporated. The residue (1.8g) was crystallized from diethyl ether. The precipitate was filtered off and dried. The residue (1.5g) was purified by kromasil column chromatography (eluent: CH)3CN/ammonium acetate 50/50; 10 μm). The two fractions were collected (F1, F2) and the solvent was evaporated. The product is as follows: 0.47g F1 and 0.44g F2. F1 crystallized from diisopropyl ether. The precipitate was filtered off and dried to obtain 0.4g of 4- [ [4- [4- (2-cyanovinyl) -2, 6-dimethylphenoxy ] phenoxy]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 255).
As already indicated above, the compounds of formula (I), (I '), (I ") or (I'") exhibit antiretroviral properties (reverse transcriptase inhibiting properties) in HIV-infected warm-blooded animals, in particular against the Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects and destroys human T-4 cells, or alters their normal function, particularly the coordination of the immune system. The result is a progressive decrease in the number of T-4 cells in infected patients and an abnormal behaviour. Thus, HIV-infected patients whose immune defense systems are unable to fight infections and neoplasms often die as a result of opportunistic infections such as pneumonia or as a result of cancer. Other diseases associated with HIV infection include thrombocytopenia, kaposi's sarcoma and central nervous system infections characterized by progressive demyelination, resulting in dementia and symptoms of progressive dysarthria, ataxia and disorientation. Furthermore, HIV infection is associated with peripheral neuropathy, Progressive Generalized Lymphadenopathy (PGL) and AIDS-related complex (ARC).
Due to their antiretroviral properties, in particular their anti-HIV-1-activity, the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, are useful for the treatment of HIV-infected individuals.
WO 2003/016306 describes the HIV replication inhibiting effect of compounds of formula (I). Test Compound 255, its pIC, was tested using the test method described in WO 2003/016306, entitled "C. pharmacological example50The value was 9.00.
It has now been found that the compounds of formula (I) can be used not only to treat warm blooded animals infected with HIV, but also to prevent HIV infection in warm blooded animals, including humans, obtained by sexual intercourse or related intimate contact between partners. Thus, as already indicated above, the present invention relates to the use of a compound of formula (I) for the preparation of a medicament for the prevention of HIV infection obtained by sexual intercourse or related intimate contact between partners, in particular for the prevention of HIV-1 infection and more particularly the prevention of HIV or HIV-1 infection with (multi) drug resistant HIV strains, i.e. HIV strains, in particular HIV-1 strains, which strains are resistant to one or more non-nucleoside reverse transcriptase inhibitors known in the art. Non-nucleoside reverse transcriptase inhibitors known in the art are those non-nucleoside reverse transcriptase inhibitors other than the present compounds, especially commercial non-nucleoside reverse transcriptase inhibitors.
The present invention also relates to a method for preventing HIV infection through sexual intercourse or related intimate contact between partners comprising administering to a patient in need thereof an effective amount of a compound of formula (I).
The term sexual intercourse or related intimate contact between partners includes vaginal, anal, oral and sexual partner contact of body parts with HIV-infected secretions, in particular semen. In particular, the term sexual intercourse or related intimate contact between partners includes vaginal, anal or oral sex, more particularly vaginal sex.
The sites of contact that should be responsible for transmission of HIV through sexual intercourse or intimate contact between partners are believed to be the genitals, rectum, mouth, hands, lower abdomen, upper thighs.
The term "companion" as referred to in the present context is defined as two or more warm blooded animals, especially humans, which are sexually behaving with each other, i.e. have intercourse with each other or have close contact in connection with sexual behaviour with each other.
The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I), characterized in that it is in a form suitable for being applied to the site of sexual intercourse or related intimate contact, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth.
As suitable compositions which may be cited, all compositions can generally be applied to the vagina, rectum, mouth and skin, for example gels, jellies (jellies), creams, ointments, films (films), sponges (sponges), foams (foams), vaginal rings, cervical caps, suppositories for rectal or vaginal application, vaginal or rectal or buccal tablets, mouthwashes.
To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is intimately admixed with a pharmaceutically acceptable carrier, which may take a wide variety of different carrier forms depending on the mode of administration. For example, in the preparation of compositions for topical intraoral administration, any of the usual pharmaceutical media may be employed, for example, in the case of oral liquid preparations such as mouthwashes in the form of suspensions, emulsions and solutions, water, glycols, oils, alcohols and the like; or in the case of tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like may be employed. Solid form preparations also include preparations which are intended to be converted to liquid form immediately prior to use. In compositions suitable for dermal administration, the carrier optionally comprises a suitable humectant, optionally in combination with a suitable minor proportion of an additive of any nature which does not have a significant deleterious effect on the skin. The additives may facilitate the administration to the skin and/or aid in the preparation of the desired composition. These compositions may be administered in different ways, such as creams or gels.
In order to extend the residence time of the pharmaceutical composition at the site of administration, it may be advantageous for the composition of the invention to comprise a bioadhesive, in particular a bioadhesive polymer. A bioadhesive may be defined as a material that adheres to a living biological surface, such as a mucosal membrane or skin tissue. The term bioadhesive is well known to those skilled in the art. The invention therefore also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), characterized in that the pharmaceutical composition is bioadhesive at the site of application. Preferred sites of application are vaginal, rectal, oral or cutaneous, most preferred is the vagina. Examples of bioadhesives that may be used in the pharmaceutical compositions of the present invention include polyacrylic acid derivatives, for example carbopol or polycarbophil, such as carbopol 934P, carbopol 940, polycarbophil AA 1; cellulose ether derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, chitosan; natural polymers such as alginates, tragacanth, inulin; pregelatinized starch.
One embodiment of the present invention relates to a gel comprising carbopol, hydroxypropyl cellulose, hydroxyethyl cellulose, or pregelatinized starch.
To aid in the dissolution of the compound of formula (I), suitable ingredients, such as cyclodextrins, may be included in the composition. Suitable cyclodextrins are alpha-, beta-, gamma-cyclodextrins or ethers and mixed ethers thereof, wherein the hydroxyl group of one or more of the anhydroglucose units of the cyclodextrin is replaced by C1-6Alkyl, especially substituted with methyl, ethyl or isopropyl, such as randomly methylated β -CD; hydroxy radical C1-6Alkyl, especially hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy group C1-6Alkyl, especially carboxymethyl or carboxyethyl; c1-6Alkylcarbonyl, especially acetyl. Of particular note as complexing and/or solubilizing agents are beta-CD, randomly methylated beta-CD, 2, 6-dimethyl-beta-CD, 2-hydroxyethyl-beta-CD, 2-hydroxypropyl-beta-CD, and (2-carboxy-beta-CDMethoxymethoxy) propyl-beta-CD, especially 2-hydroxypropyl-beta-CD (2-HP-beta-CD).
The term mixed ether denotes cyclodextrin derivatives in which at least two cyclodextrin hydroxy groups are etherified with different groups (e.g. hydroxypropyl and hydroxyethyl).
A measure of the average molar number of alkoxy units per mole of anhydroglucose that the average molar substitution (m.s.) is used for. The average degree of substitution (d.s.) refers to the average number of hydroxyl groups substituted per anhydroglucose unit. The m.s. and d.s. values can be determined by various analytical techniques such as Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS) and infrared spectroscopy (IR). It is possible for a given cyclodextrin derivative to obtain different values with minor differences depending on the technique used. Preferably, the m.s. ranges from 0.125 to 10 and the d.s. ranges from 0.125 to 3 as determined by mass spectrometry.
The compounds of formula (I) may be formulated in the pharmaceutical compositions of the present invention in the form of microparticles formed from a solid dispersion comprising a compound of formula (I) and one or more suitable pharmaceutically acceptable water-soluble polymers.
The term "solid dispersion" as used hereinafter is defined as a system in a solid state (not a liquid or gaseous state) comprising at least two components, e.g. a compound of formula (I) and a water-soluble polymer, wherein one component is more or less uniformly dispersed in the other component or components, including other pharmaceutically acceptable formulating agents well known in the art, e.g. plasticizers, preservatives, etc. When the dispersion of the components is a system which is chemically and physically homogeneous or homogeneous throughout or which consists of a phase as defined in thermodynamics, such a solid dispersion is called a "solid solution". Solid solutions are preferred physical systems because the components therein are generally readily bioavailable to the organ they are intended to act upon. This advantage is illustrated by the fact that the solid solution can readily form a liquid solution when contacted with a liquid medium, such as gastrointestinal fluids. The ease of dissolution may be due, at least in part, to the fact that the energy required to dissolve the solid solution component is less than the energy required to dissolve the crystalline or microcrystalline solid phase component.
The term "solid dispersion" also includes those dispersions that are less homogenous than a solid solution. These dispersions are chemically and physically heterogeneous throughout or contain more than one phase. For example, the term "solid dispersion" also relates to a system having a region or small domain in which a non-crystalline, microcrystalline or crystalline compound of formula (I), or a non-crystalline, microcrystalline or crystalline water-soluble polymer, or both, are more or less uniformly dispersed in another phase comprising a water-soluble polymer, or a compound of formula (I), or in a solid solution comprising a compound of formula (I) and a water-soluble polymer. The domains refer to the clearly differentiated ranges in the solid dispersion by some physical properties, small size and uniformly and randomly distributed throughout the solid dispersion.
There are various techniques for preparing solid dispersions, including melt-extrusion, spray-drying and solution-evaporation.
The dissolution-dehydration process comprises the following steps;
a) dissolving a compound of formula (I) and a water-soluble polymer in a suitable solvent, optionally at elevated temperature;
b) optionally heating the solution obtained in a) under vacuum until the solvent is evaporated. The solution can also be poured onto a large surface to form a thin film to evaporate the solvent.
In the spray-drying technique, both components are dissolved in a suitable solvent and the resulting solution is then sprayed through the nozzle of a spray dryer, the solvent in the droplets produced by the spraying being evaporated at elevated temperature.
A preferred technique for preparing the solid dispersion is a melt-extrusion process comprising the steps of:
a) mixing a compound of formula (I):
b) mixing the mixture thus obtained with optional additives;
c) heating and compounding the mixture thus obtained until a homogeneous melt is obtained;
d) forcing the melt thus obtained through one or more nozzles; then the
e) The melt is cooled until it solidifies.
The terms "melt" and "melted" should be interpreted broadly. These terms not only denote a transition from the solid state to the liquid state, but also a transition from the solid state to the glassy state or rubbery state, and where for one component of the mixture it is also possible to mean a more or less homogeneous embedding in the other component. In a particular example, one component is melted and the other component is dissolved in the melt to form a solution, which upon cooling can form a solid solution with advantageous dissolution characteristics.
After preparation of the solid dispersion as described above, the product obtained may optionally be milled and sieved.
The solid dispersion product may be milled or ground into particles having a particle size of less than 600 μm, preferably less than 400 μm and most preferably less than 125 μm.
The microparticles prepared as described above may then be formulated into pharmaceutical dosage forms of the present invention by conventional techniques.
It will be appreciated that the skilled person will be able to optimise the parameters of the solid dispersion preparation technique as described above, such as the most suitable solvent, operating temperature, type of apparatus used, frequency of spray-drying, throughput of melt-extrusion.
The water-soluble polymer in the fine particles is a polymer having an apparent viscosity of 1 to 5000mPa.s, preferably 1 to 700mPa.s, most preferably 1 to 100mPa.s when dissolved in a 2% (w/v) aqueous solution at 20 ℃. For example, suitable water-soluble polymers include alkyl celluloses, hydroxyalkyl alkyl celluloses, carboxyalkyl celluloses, alkali metal salts of carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters, starches, pectins, chitin derivatives, disaccharides, oligosaccharides and polysaccharides such as trehalose, alginic acid or alkali metals and its ammonium salts, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylic acid copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of vinyl acetate and polyvinylpyrrolidone, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. The preferred water soluble polymer is hydroxypropyl methylcellulose.
As disclosed in WO 97/18839, one or more cyclodextrins may also be used as water-soluble polymers for the preparation of the above-mentioned microparticles. The cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, in particular alpha, beta or gamma cyclodextrins or their pharmaceutically acceptable derivatives.
Substituted cyclodextrins that can be used to prepare the microparticles described above include polyethers described in U.S. Pat. No. 3,459,731. The further substituted cyclodextrin is one or more of the hydrogens on the hydroxyl groups of the cyclodextrin replaced by C1-6Alkyl, hydroxy C1-6Alkyl, carboxy-C1-6Alkyl or C1-6Alkoxycarbonyl group C1-6Alkyl-substituted ethers or mixtures of these ethers. In particular substituted cyclodextrins in which one or more of the hydrogens of the cyclodextrin hydroxyl groups are replaced by C1-3Alkyl, hydroxy C2-4Alkyl or carboxyl C1-2Alkyl-substituted ethers, or more particularly ethers substituted by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.
Of particular interest are β -cyclodextrin ethers such as the dimethyl- β -cyclodextrin described by m.nogradi (1984) in Drugs oft he Future, vol.9, No. 8, page 577-578, and examples of polyethers such as hydroxypropyl β -cyclodextrin and hydroxyethyl β -cyclodextrin. Such alkyl ethers may be methyl ethers with some degree of substitution of about 0.125 to 3, for example about 0.3 to 2. Such hydroxypropyl cyclodextrins may be formed from the reaction of beta-cyclodextrin and propylene oxide and may have an MS value of about 0.125 to 10, for example about 0.3 to 3.
Another class of substituted cyclodextrins is the sulfobutylcyclodextrins.
The ratio of the compound of formula (I) to the water-soluble polymer may vary widely, for example ratios 1/100 to 100/1 may be used. Important ratios of the compound of formula (I) to cyclodextrin range from about 1/10 to 10/1. A more important ratio range is about from 1/5 to 5/1.
The effective daily amount can be determined by those skilled in the prevention of HIV infection from the test results presented herein. The exact dosage will depend upon the particular compound of formula (I) used.
To increase the protective effect against HIV infection, the compounds of formula (I) may also be combined with one or more other antiretroviral compounds. Accordingly, the present invention also provides a pharmaceutical composition according to the invention comprising a compound of formula (I) and further comprising one or more additional antiretroviral compounds. The invention also relates to a product containing (a) a compound of formula (I), and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in the prevention of HIV infection. The different drugs may be combined together with a pharmaceutically acceptable carrier into a single formulation. The additional antiretroviral compound may be a known antiretroviral compound such as suramin, pentoxybenzimidazole, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphonoformate); nucleoside reverse transcriptase inhibitors such as azidothymidine (3 '-azido-3' -deoxythymidine, AZT), didanosine (2 ', 3' -dideoxyinosine)Oxyinosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (2 '-3' -dideoxy-3 '-thiamine cytidine (thiacytidine), 3TC), stavudine (2', 3 '-didehydro-3' -deoxythymidine, d4T), abacavir, etc.; non-nucleoside reverse transcriptase inhibitors such as nevirapine (11-cyclopropyl-5, 11-dihydro-4-methyl-6H-bipyridino- [3, 2-b: 2 ', 3' -e)][1，4]Diaza derivatives-6-ketone), efavirenz, delavirdine, TMC-120, TMC-125, etc.; phosphonate reverse transcriptase inhibitors such as tenofovir and the like; TIBO compounds (tetrahydro-imidazo [4, 5, 1-jk)][1，4]-benzodiazepines-2(1H) -ketones and thiones) such as (S) -8-chloro-4, 5,6, 7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo- [4, 5, 1-jk][1，4]-benzodiazepines-2(1H) -thione; alpha-APA (alpha-anilinophenylacetamides) compounds such as alpha- [ (2-nitrophenyl) amino]-2, 6-dichlorobenzene-acetamide, and the like; trans-activator protein inhibitors, for example TAT-inhibitors such as RO-5-3335, or REV inhibitors and the like; protease inhibitors such as indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, amprenavir, TMC-126, BMS-232632, VX-175, etc.; fusion inhibitors such as T-20, T-1249 and the like; CXCR4 receptor antagonists such as AMD-3100 and the like; inhibitors of viral integrase; nucleoside-like reverse transcriptase inhibitors such as tenofovir and the like; ribonucleotide reductase inhibitors such as hydroxyurea and the like.
The prophylactic effects of the compounds of the invention can be enhanced by co-administration of these compounds with other antiviral agents that act on different events in the viral life cycle. Because each component of the combination acts at a different site of HIV replication, the combination therapies described above can produce a synergistic effect in inhibiting HIV replication. The use of such a combination may reduce the dosage of a given conventional antiretroviral drug required to achieve the desired prophylactic effect, as compared to administration of the drug as a monotherapy. These combinations reduce the likelihood of drug resistance on monotherapy and minimize any associated toxicity. These combinations may also improve their effectiveness without increasing the toxicity associated with conventional drugs.
In addition to the combinations of the compounds of the present invention described above and one or more other antiretroviral agents, the compounds of the present invention may also be administered in combination with microbicides known in the art. They can create a barrier carrier between the pathogen (here the human immunodeficiency virus) and the site where transmission of the infection will occur, e.g. the vagina, to block the infection; they can kill or immobilize pathogens; they can prevent the virus from replicating as soon as it infects cells arranged at the site of propagation, for example, on the vaginal wall. Examples of microbicides are:
a) an antibody. Scientists have discovered methods to isolate neutralizing HIV antibodies and to produce antibodies in large quantities. Thus, these HIV antibodies can be used in combination with the compounds of formula (I) of the present invention to prevent HIV infection.
b) Detergents and surfactants. These compounds are capable of disrupting the viral coat and are therefore useful as microbicides, and they are capable of preventing HIV infection in combination with the compounds of formula (I) of the present invention. Examples of such detergents and surfactants are nonoxynol-9 and octoxynol-9, but all detergents and surfactants which are routinely used in shampoos, toothpaste and cleaning solutions, and contact lens solutions are equally suitable.
c) Coatings (coatings) of the site of transmission, i.e. of the administration site of the pharmaceutical composition, for example gels. These products can prevent HIV from entering the cell lining at the site of transmission, such as the lining the vagina. Examples are sulfated and sulfonated polymers such as PC-515 (carrageenan), Pro-2000, dextrin 2 sulfate.
d) Peptides. Peptides are small protein molecules that line every surface of the human body, such as the skin, tongue, intestinal tract, and they kill pathogens within minutes of exposure. Thus, peptides, if used at sites where HIV is likely to transmit, can kill pathogens before they cause infection.
e) A pH regulator, in particular for vaginal use. These compounds modulate the natural acidity of the vagina, making it unsuitable for HIV survival. The natural vaginal environment is too acidic for HIV to survive, but semen is alkaline, which increases vaginal alkalinity during sexual intercourse, allowing HIV to survive. The alkaline environment caused by semen can be neutralized by the use of a PH adjuster compound. The use of pH modifiers includes the use of lactobacilli, which produce hydrogen peroxide and thereby help maintain vaginal health and acidity.
In the compositions of the present invention, one or more or all of the above-listed classes of microbicides can be used in combination with a compound of formula (I). Accordingly, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and further comprising one or more components selected from the group consisting of antibodies, detergents or surfactants, coatings on the administration site of the pharmaceutical composition, peptides, PH modifiers. The invention also relates to a product comprising (a) a compound of formula (I), and (b) one or more components selected from antibodies, detergents or surfactants, coatings for the administration site of pharmaceutical compositions, peptides, PH modifiers, as a combined preparation for simultaneous, separate or sequential use in the prevention of HIV infection. The different drugs may be combined into a single agent together with a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition, as described above, which further comprises a spermicidal compound. The composition is capable of preventing pregnancy and HIV infection simultaneously. Suitable spermicides include nonoxynol-9, octoxynol-9, euphorbia, benzalkonium chloride, and N-docosanol.
Although the focus of the present invention is on the use of the compounds of the present invention to prevent HIV infection through sexual intercourse or related intimate contact between partners, these compounds may also be used as inhibitors to prevent infection by other viruses that must rely on similar reverse transcriptase in their life cycle.
Examples
The following tables 1, 2 and 3 list the compounds of formula (I).
TABLE 1：
Compound numbering R3 R4 Physical data mp. ℃/(MH +)*
2 2-benzofuranyl radical H mp.＞240
21 3-thienyl radical H mp.220
3 2-furyl radical H mp.228
28 2-thienyl radical H mp.235
29 Phenyl radical H mp.230
1 -CH＝CH-CN H mp.245，(E)
30 2, 4-dichlorophenyl H (460)
31 2-benzene [ b ]]Thienyl radical H (448)
32 1-naphthyl radical H (442)
33 3-chlorophenyl group H (426)
34 3-acetylphenyl H (434)
35 3-methylphenyl radical H (406)
36 2-naphthyl radical H (442)
37 4-chlorophenyl group H (426)
*(MH+) Defined as the amount of protonated compound; measured by a MicroMass spectrometer equipped with an electrospray probe and a four-polar analyzer.
TABLE 2：
*(MH+) Defined as the amount of protonated compound; measured by a MicroMass spectrometer equipped with an electrospray probe and a four-polar analyzer.
TABLE 3：
Pharmacological examples
A)Test compounds prevent HIV perception through sexual intercourse or related intimate contact between partners In vitro model of staining Capacity。
To illustrate the ability of the compounds of the present invention to prevent HIV infection through sexual intercourse or related intimate contact between partners, the compounds of formula (I) were tested in the following assays. Naive monocyte-derived dendritic cells (immMO-DCs) are a good model to represent interstitial dendritic cells, which are the target cells in the early stages of sexual transmission of HIV and are important initiators of the immune response. These immMO-DCs were used in an "in vitro" model to test the prophylactic effect on HIV infection obtained by sexual intercourse or related intimate contact between partners.
In vitro model a)
The uniphilic HIV strain Ba-L was pre-incubated with a compound of formula (I) (test compound). immMO-DC was added to the mixture of virus and test compound and incubated at 37 ℃ for 2 hours. After infection, the cells were washed 6 times and cultured with autologous CD4(+) T cells (ratio immMO-DC/CD4(+) T: 1/10). The test compound was added again and maintained during 14 days of primary culture, and PHA (phytohaemagglutinin)/IL-2 (interleukin-2) -stimulated blasts (subculture, no test compound) were added after sufficient washing of the cells. Supernatants from primary and secondary cultures were analyzed by ELISA. Antiviral activity was determined by measuring the concentration of test compound that inhibited 50% of viral replication at the end of primary culture (EC 50). In addition, cells were collected after 3 weeks of subculture, and the amount of HIV proviral DNA present was analyzed (PCR), checked for sterilization and virus reactivation was excluded.
In vitro model b) (24 hours infection test)
Monocyte-derived dendritic cells (MO-DC) were co-cultured with autologous T4 cells and were treated with HIV strain Ba-L as 10-3Multiplicity of infection (MOI) infection. A series of dilutions of the test compound were added at the time of infection. After 24 hours, the 96-well plates were washed 3 times (to wash out test compound and free virus) and medium (without test compound) was added. Half of the medium was changed twice a week and culture supernatants were collected at 7 and 14 days of culture. After 14 days, the cultures were washed 3 times and subcultured with PHA/IL-2-stimulated PBMC (peripheral blood mononuclear cells) to check for virus reactivation. During the subculture, half of the medium (IL-2 medium, without test compound) was renewed twice a week. Supernatants were collected after 1 and 2 weeks of subculture. Cells were also harvested for PCR analysis after 2 weeks of subculture. The amount of HIV proviral DNA present in the supernatant was analyzed by ELISA both in primary and secondary cultures.
After 7 days of primary culture, none of the ELISA tests of Compound 230 was positive at six well (cups) concentrations ranging from 10,000 to 100 nM. After 7 days of primary culture, none of the ELISA tests of compound 255 at six well concentrations ranging from 10,000 to 10nM were positive.
In vitro model c) (Standard infection test)
10 + using the uniphilic HIV strain Ba-L3Multiplicity of infection (MOI) of monocyte-derived dendritic cells (MO-DC) for 2 hours. Cells were washed 6 times after infection and suspended in 10% BCS at a concentration of 400.000 cells/ml. Autologous CD4(+) T cells were isolated and purified from the same fraction of lymphocytes as the MO-DC from the same eluate at 2X 106The concentration of individual cells/ml (ratio MO-DC/CD4(+) T: 1/5) was used.
A dilution series of compounds of formula (I) (test compounds) was added to co-cultures of MO-DC/CD4(+) T cells. Each assay was performed in 96 well culture plates, each well containing 50. mu.l MO-DC, 50. mu.l CD4(+) T cells, and 100. mu.l test compound. Half of the medium containing the test compound was refreshed twice a week for 14 days. After 14 days of culture the supernatants were analyzed for the amount of HIV antigen present by ELISA. Antiviral activity was determined by measuring the concentration of test compound that inhibited 50% of viral replication at the end of primary culture (EC 50).
B)Testing of Mixed Leukocyte Cultures (MLC) for immunosuppressive Activity of Compounds of the invention。
The immunosuppressive activity of the compounds of formula (I) (defined as ISC) was tested in a typical MLC in which monocyte-derived dendritic cells (MO-DCs) were used as stimulators and the same CD4(+) T cells were used as responders (responders)50Value).
A series of dilutions of the test compound were added to co-cultures of MO-DC/CD4(+) T cells. After 5 days of culture, [ methyl-3H]Thymidine 20. mu.l, and the culture broth was collected after 7 hours. Analyzed by a Topcount scintillation counter. Immunosuppressive concentration (ISC)50) Defined as the concentration of test compound that inhibits 50% of normal immune proliferation (50% inhibition [ methyl-3H]Concentration of test compound for thymidine (incorporation). (Standard MLC test method)
In the 24 hour assay, test compounds only appeared during the first 24 hours of the 5 day incubation period. After 24 hours, the medium was rinsed (3 times) and a compound-free medium was added. The protocol of the experiment from then on is similar to the standard MLC assay described above.
Tables 4 and 5 list the results obtained from the above-mentioned test methods. The conclusion drawn from these results is that the test compounds effectively blocked HIV infection in MO-DC/CD4(+) T cell co-culture medium. Immunosuppression is only found at very high concentrations. Thus, the compounds of the present invention may be considered as novel microbicides.
TABLE 4：
Compound number EC50(nM) (in vitro model c) ISC50(nM) (B test, Standard test)
248 0.55 1,5553
24 0.55 675
151 2 385
231 3 18,690
1 0.42 1,216
230 0.24 43,208
162 5.5 1,141
250 3 4,500
242 3
255 0.05 20,240
TABLE 5：
Compound number EC50(nM) (in vitro model b) ISC50(nM) (B test, 24 hours test)
1 1 22,221
230 8 ＞100,000
255 2 24,635

Claims (22)

1. Use of a compound for the manufacture of a medicament for the prevention of HIV infection obtained by sexual intercourse or related intimate contact between partners, wherein the compound, N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof has the formula
Wherein
-a1＝a2-a3＝a4-represents a divalent radical of formula
-CH＝CH-CH＝CH- (a-1)；
-N＝CH-CH＝CH- (a-2)；
-N＝CH-N＝CH- (a-3)；
-N＝CH-CH＝N- (a-4)；
-N＝N-CH＝CH- (a-5)；
-b1＝b2-b3＝b4-represents a divalent radical of formula
-CH＝CH-CH＝CH- (b-1)；
-N＝CH-CH＝CH- (b-2)；
-N＝CH-N＝CH- (b-3)；
-N＝CH-CH＝N- (b-4)；
-N＝N-CH＝CH- (b-5)；
n is 0, 1, 2, 3 or 4; and is in-a1＝a2-a3＝a4In case of-being (a-1), then n can also be 5;
m is 1, 2, 3, and in-b1＝b2-b3＝b4In the case of (b-1), m may also be 4;
R1is hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy substituted C1-6An alkyl group; quilt C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
each R2Independently is hydroxy, halo, optionally cyano or-C (═ O) R6Substituted C1-6Alkyl radical, C3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkynyl, C1-6Alkoxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino, polyhalomethyl, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6Or a group of the formula
Wherein each A1Independently N, CH or CR6(ii) a And
A2is NH, O, S or NR6；
X1is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、C1-4Alkanediyl, -CHOH-, -S (═ O)P-、-X2-C1-4alkanediyl-or-C1-4alkanediyl-X2-；
X2is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-CHOH-、-S-、-S(＝O)P-；
R3Is NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；
-CH＝N-NH-C(＝O)-R16(ii) a Is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkyl, and wherein 2 hydrogen atoms bonded to the same carbon atom are replaced by C1-4Alkanediyl substitution; by hydroxy and a second group selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halo, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；
X3is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-S-、-S(＝O)P-、-X2-C1-4Alkanediyl-, -C1-4alkanediyl-X2a-、-C1-4alkanediyl-X2b-C1-4Alkanediyl, -C (═ N-OR)8)-C1-4Alkanediyl-;
wherein X2ais-NH-NH-, -N-, -O-, -C (O) -, -S (O)P-；
And the combination of (a) and (b),
X2bis-NH-NH-, -N-, -C (O) -, -S (O)P-；
R4Is halo, hydroxy, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy, cyano, nitro, polyhaloC1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyl, formyl, amino, mono-or di (C)1-4Alkyl) amino or R7；
R5Is hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl or C1-6Alkylcarbonyloxy substituted C1-6An alkyl group; quilt C1-6Alkoxycarbonyl substituted C1-6Alkoxy radicalRadical C1-6An alkylcarbonyl group;
R6is C1-4Alkyl, amino, mono-or di (C)1-4Alkyl) amino or polyhaloC1-4An alkyl group;
R7is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents, each substituent being independently selected from halo, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8)、R7a、-X3-R7aOr R7a-C1-4An alkyl group;
R7ais a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents, each substituent being independently selected from halo, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8)；
R8Is hydrogen, C1-4Alkyl, aryl or aryl C1-4An alkyl group;
R9and R10Each independently is hydrogen; a hydroxyl group;C1-6an alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein each of the above C1-6The alkyl groups may be optionally and independently substituted with one or two substituents each independently selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7(ii) a Or
R9And R10May be combined together to form a divalent or trivalent radical of the formula
-CH2-CH2-CH2-CH2- (d-1)
-CH2-CH2-CH2-CH2-CH2- (d-2)
-CH2-CH2-O-CH2-CH2- (d-3)
-CH2-CH2-S-CH2-CH2- (d-4)
-CH2-CH2-NR12-CH2-CH2- (d-5)
-CH2-CH＝CH-CH2- (d-6)
＝CH-CH＝CH-CH＝CH- (d-7)
R11Is cyano; optionally is covered with C1-4Alkoxy, cyano, amino, mono-or di (C)1-4Alkyl) amino or aminocarbonyl substituted C1-4An alkyl group; c1-4An alkylcarbonyl group; c1-4An alkoxycarbonyl group; an aminocarbonyl group; mono-or di (C)1-4Alkyl) aminoA carbonyl group;
R12is hydrogen or C1-4An alkyl group;
R13and R14Each independently being C optionally substituted by cyano or aminocarbonyl1-6Alkyl, C optionally substituted by cyano or aminocarbonyl2-6Alkenyl, C optionally substituted by cyano or aminocarbonyl2-6An alkynyl group;
R15is C substituted by cyano or aminocarbonyl1-6An alkyl group;
R16is C optionally substituted by cyano or aminocarbonyl1-6Alkyl, or is R7；
p is 1 or 2;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents, each substituent being independently selected from halo, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, R7or-X3-R7。
2. Use of a compound according to claim 1, wherein the compound has the formula
Wherein
-a1＝a2-a3＝a4-、-b1＝b2-b3＝b4-、R1、R2、R3、R4M and X1As defined in claim 1; n' is 0, 1, 2 or 3 at-a1＝a2-a3＝a4In the case of (a-1), n' may also be 4; r2' is halogeno, C1-6Alkyl, trihalomethyl, trihalomethoxy, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group;
provided that R is2In relation to NR1And (4) partial alignment.
3. Use of a compound according to claim 1 or 2, wherein the compound has the formula
Wherein
-b1＝b2-b3＝b4-、R1、R2、R3、R4M and X1As defined in claim 1; n' and R2' as defined in claim 3.
4. Use of a compound according to any one of claims 1 to 3, wherein the compound has the formula
Wherein R is1、R2、R3、R4And X1As defined in claim 1; n' and R2' as defined in claim 3.
5. Use of a compound according to any one of claims 2 to 4, wherein R2' is cyano, aminocarbonyl or C substituted by cyano or aminocarbonyl1-6An alkyl group.
6. Use of a compound according to any one of claims 1 to 5, wherein said compound is selected from
4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile;
4- [ [4- [4- (2-cyanovinyl) -2, 6-dimethylphenoxy ] -2-pyrimidinyl ] amino ] benzonitrile;
4- [ [4- [4- [ 2-cyanovinyl ] -2-methylphenoxy ] -2-pyrimidinyl ] amino ] benzonitrile; an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.
7. Use according to claim 6, wherein the compound is selected from
4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E);
4- [ [4- [4- (2-cyanovinyl) -2, 6-dimethylphenoxy ] -2-pyrimidinyl ] amino ] benzonitrile (E);
4- [ [4- [4- [ 2-cyanoethenyl ] -2-methylphenoxy ] -2-pyrimidinyl ] amino ] benzonitrile (E).
8. Use according to any one of claims 1 to 7, wherein the sexual intercourse is a vaginal, anal or oral sexual intercourse.
9. Use according to claim 8, wherein the sexual intercourse is a vaginal intercourse.
10. Use according to any one of claims 1 to 9 wherein the medicament is in a form suitable for application at the site of sexual intercourse or related intimate contact between partners.
11. Use according to claim 10, wherein the medicament is in a form suitable for application to the vagina, rectum, mouth or skin.
12. Use according to claim 11, wherein the medicament is in the form of a gel, jelly, cream, ointment, film, sponge, foam, vaginal ring, cervical cap, suppository for rectal or vaginal application, vaginal or rectal or buccal tablet, mouthwash.
13. Use according to any one of claims 1 to 12, wherein the HIV infection is a multidrug resistant HIV infection.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as defined in any one of claims 1 to 7, characterized in that the pharmaceutical composition is bioadhesive to the site of application.
15. A pharmaceutical composition as claimed in claim 14 wherein the site of application is the vagina, rectum, mouth or skin.
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as defined in any one of claims 1 to 7, characterized in that the pharmaceutical composition is in a form suitable for vaginal or oral application.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 7, characterized in that it is in the form of a gel, jelly, cream, film, sponge, foam, pessary, cervical cap, suppository for rectal or vaginal application, vaginal or rectal or buccal tablet, mouthwash.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as defined in any one of claims 1 to 7, characterized in that the pharmaceutical composition is in the form of a gel comprising carbopol, hydroxypropyl cellulose, hydroxyethyl cellulose or pregelatinized starch.
19. A pharmaceutical composition as claimed in any one of claims 14 to 18 which further comprises one or more additional antiretroviral compounds.
20. A pharmaceutical composition as claimed in any one of claims 14 to 19 which further comprises one or more components selected from antibodies, detergents or surfactants, coatings of the site of administration of the pharmaceutical composition, peptides or PH modifiers.
21. A pharmaceutical composition as claimed in any one of claims 14 to 20 which further comprises a spermicidal compound.
22. A compound of formula (I) as defined in claim 1, wherein said compound is
An N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.
HK12101603.3A 2003-02-07 2012-03-16 Pyrimidine derivatives for the prevention of hiv infection HK1161092A (en)

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Application Number Priority Date Filing Date Title
EPPCT/EP03/01291 2003-02-07

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Publication Number Publication Date
HK1161092A true HK1161092A (en) 2012-08-24

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