Novel compounds of the formula I

The invention relates to compounds of the formula I
in which
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94Nh2 which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group,
R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
R3 is A, cycloalkyl, xe2x80x94[C(R6)2]nAr, xe2x80x94[C(R6)2]nxe2x80x94Oxe2x80x94Ar, xe2x80x94[C(R6)2]nHet or xe2x80x94C(R6)2xe2x95x90C(R6)2xe2x80x94Ar,
R6 is H, A or benzyl,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94C(R6)2xe2x80x94, xe2x80x94C(R6)2xe2x80x94C(R6)2xe2x80x94, xe2x80x94C(R6))2xe2x80x94COxe2x80x94, xe2x80x94C(R6)2xe2x80x94C(R6)2xe2x80x94COxe2x80x94, xe2x80x94C(R6)xe2x95x90C(R6)xe2x80x94COxe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94N{[C(R6)2]nxe2x80x94COOR6}xe2x80x94Oxe2x80x94 or xe2x80x94C(COOR6)R6xe2x80x94O(R6)2xe2x80x94COxe2x80x94,
Y is xe2x80x94C(R6)2xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94CONR6xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups can be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms can be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94OH2 and/or carbonyl oxygen,
Hal is F, Cl, Br or I,
n is 0, 1 or 2,
and salts thereof.
The invention also provides the optically active forms, the racemates, the diastereomers and the hydrates and solvates of these compounds.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for preparing medicaments.
It has been found that the compounds of the formula I and their salts have very useful pharmacological properties, coupled with good tolerability. In particular, they have factor Xa-inhibiting properties and can therefore be employed for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
Aromatic amidine derivatives having antithrombotic action are known, for example, from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165. Aromatic heterocycles having factor Xa-inhibiting activity are known, for example, from WO 96/10022.
The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibiting action on the activated coagulation protease, known under the name factor Xa. Factor Xa is one of the proteases which is involved in the complex process of blood coagulation. Factor Xa catalyses the conversion of prothrombin into thrombin which in turn contributes to thrombus formation. An activation of thrombin can result in the occurrence of thromboembolic disorders. Inhibition of factor Xa can thus prevent thrombin formation. The compounds of the formula I according to the invention and their salts intervene in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
The inhibition of factor Xa by the compounds according to the invention and the measurement of the anti-coagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 63, 220-223 (1990).
The inhibition of factor Xa can be determined, for example, by the method of T. Hara et al. in Thromb. Haemoscas. 71, 314-319 (1994).
The compounds of the formula I can be employed as medicaments in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myoca-dial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
The invention provides the compounds of the formula I and their salts, and also a process for preparing compounds of the formula I according to Claim 1 and their salts, characterized in that
a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by
i) liberating an amidino group from its oxadiazole derivative by hydrogenolysis,
ii) replacing a conventional amino-protective group by treatment with a solvolysing or hydrogenolysing agent with hydrogen or liberating an amino group which is protected by a conventional protective group, or
b) that for preparing compounds of the formula I
in which
R1 is
X is xe2x80x94COxe2x80x94 or xe2x80x94C(R )2xe2x80x94COxe2x80x94,
and R2, R3 and Y are as defined in Claim 1,
xe2x80x83a compound of the formula II
in which
R3, R4, R5, W and Y are as defined in Claim 1,
xe2x80x83is reacted with a compound of the formula III
in which
R1 is
X is xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94COxe2x80x94,
R2 is as defined in Claim 1,
and L is Cl, Br, I or a free or a reactive functionally derivatized OH group, or
c) that for preparing compounds of the formula I
in which
R1 is
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94,
and R2 and X are as defined in Claim 1,
xe2x80x83a compound of the formula IV
Lxe2x80x94Yxe2x80x94R3xe2x80x83xe2x80x83IV
in which
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94,
R3 is as defined in Claim 1, and L is Cl, Br, I or a free or a reactive functionally derivatized OH group,
xe2x80x83is reacted with a compound of the formula V
in which
R1 is
and R2 and X are as defined in Claim 1, or
d) that for preparing compounds of the formula I
in which
R1 is
Y is xe2x80x94CONHxe2x80x94,
and R2 and X are as defined in Claim 1,
xe2x80x83a compound of the formula VI
R3xe2x80x94N=C=Oxe2x80x83xe2x80x83VI
in which
R3 is as defined in Claim 1,
xe2x80x83is reacted with a compound of the formula V
in which
R1 is
and R2 and X are as defined in Claim 1, or
e) that for preparing compounds of the formula I
in which
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2,
a cyano group is converted into an amidino group,
f) and/or that in a compound of the formula I, one or more radicals R1, R2 and/or R3 are converted into one or more radicals R1, R2 and/or R3 by, for example,
i) hydrolysing an ester group to give a carboxyl group,
ii) reducing a nitro group,
iii) acylating an amino group,
g) and/or converting a base or acid of the formula I into one of its salts.
For all the radicals which occur several times, such as, for example, R6, the meanings thereof are independent of one another.
Hereinabove and hereinbelow, the radicals or parameters L, X, Y, R1, R2 and R3 have the meanings given for the formulae I to VI, unless expressly stated otherwise.
In the above formulae, A is alkyl and has 1 to 20, preferably 1, 2, 3, 4. 5, 6, 7, 8, 9, 10, 11 or 12 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl. Alkyl is furthermore, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl is in particular the radical of a bicyclic terpene, such as, for example, 3-menthyl; very particular preference is given to the camphor-10-yl radical.
COR6 is acyl and is preferably formyl, acetyl, propionyl, furthermore also butyryl, pentanoyl or hexanoyl.
Hal is preferably F, Cl or Br, but also I.
R2 is preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ehylamino, diethyl-amino, acetamido, sulphonamido, methylsulphonamido, phenylsulphonamido, methylthio, ethylthio, methyl-sulphinyl, ethylsulphinyl, methylsulphonyl, ethyl-sulphonyl, phenylsulphinyl, phenylsulphonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, furthermore also acyl or benzoyl.
R3 is preferably, for example, A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CHxe2x95x90CH-Ar.
R6 is H, A or benzyl, but preferably H.
X is preferably, for example, absent, xe2x80x94COxe2x80x94, xe2x80x94OH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH=CHxe2x80x94COxe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94N{[CH2]nCOOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94.
Y is preferably, for example, xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94, furthermore also xe2x80x94COOxe2x80x94, xe2x80x94CONHxe2x80x94 or xe2x80x94CH2xe2x80x94.
Ar is preferably unsubstituted phenyl or naphthyl, furthermore preferably naphthyl or phenyl which is mono-, di- or trisubstituted, for example by A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl, phenylsulphinyl, phenylsulphonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulphonamido, ethylsulphonamido, propylsulphonamido, butylsulphonamido, phenylsulphonamido, (4-methylphenyl)sulphonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonyl-ethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl or benzoyl, furthermore also biphenyl.
Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-acetamidophenyl, o-, m-or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylsulphonylphenyl, o-, m- or p-(phenyl-sulphonamido)phenyl, o-, m- or p-(methylsulphonamido)phenyl, o-, m- or p-methylthiophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-, or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Ar is very particularly preferably unsubstituted phenyl or naphthyl, furthermore preferably, for example, phenyl or naphthyl which is mono-, di- or trisubstituted by A, chlorine, methoxy, amino or dimethylamino, or is furthermore also biphenyl.
Arxe2x80x2 is in particular, for example, phenyl or naphthyl, furthermore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, nm- or p- (N,N-diethylamino)phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl or c-, m- or p-methylsulphonylphenyl.
Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-.imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, S-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo[(1,4]oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl or dibenzofuranyl. The heterocyclic radicals may also be partially or fully hydrogenated. Het may also be, for example, 2,3-dihydro-2-, -3-, -4-or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-Furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3-or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo[1,4]oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl, 2,3-(2-oxo-methylenedioxy)phenyl or else 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR , CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH . xe2x80x9cPolyxe2x80x9d means di, tri, tetra or penta.
The compounds of the formula I may have one or more chiral centres and may therefore be present in various stereoisomeric forms. The formula I embraces all of these forms.
Consequently, the invention provides in particular those compounds of the formula I in which at least one of the abovementioned radicals has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following moieties Ia to If which correspond to the formula I and where the radicals which are not defined more specifically have the meaning given for the formula I, but where
in Ia
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]n xe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group,
R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
R3 is A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N(CH2COOR6)xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or poly-substituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen,
Hal is r, Cl, Br or I and
n is 0, 1 or 2;
in Ib
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group,
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr,
xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH=CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N(CH2COOR6)xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, NH2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or poly-substituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in Ic
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group,
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr, xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH=CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR )xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R5)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole or benzothiophene,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in Id
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group,
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr, xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is phenyl,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in Ie
R1 is xe2x80x94C(xe2x95x90NH,)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group,
R2 is H,
R3 is A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR 6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is phenyl,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in If
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2 which can also be monosubstituted by COOA,
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr, xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{(CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is phenyl,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R )2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran,
Hal is F, Cl, Br or I and
n is 0, 1 or 2.
The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under the reaction conditions which are known and suitable for the reactions mentioned. In these reactions, variants which are known per se and are not mentioned here in more detail can also be utilized.
If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating the compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but, instead of one or more free amino and/or hydroxyl groups, contain corresponding protected amino and/or hydroxyl groups, preferably those which, instead of an H atom which is bonded to an N atom, carry an amino-protective group, in particular those which, instead of an HN group, carry an Rxe2x80x2-N group, in which Rxe2x80x2 is an amino-protective group, and/or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl-protective group, for example those which correspond to the formula I but, instead of a xe2x80x94COOH group, carry a group xe2x80x94COORxe2x80x3, in which Rxe2x80x3 is a hydroxyl-protective group.
Preferred starting materials also include the oxadiazole derivatives which can be converted into the corresponding amidino compounds.
The introduction of the oxadiazole group is effected, for example, by reacting the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic ester, N,Nxe2x80x2-carbonyldiimidazole or acetic anhydride.
It is also possible for severalxe2x80x94identical or differentxe2x80x94protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups present differ from one another, in many cases they can be cleaved off selectively.
The term xe2x80x9camino-protective groupxe2x80x9d is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out at other sites of the molecule. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8 C atoms are preferred. The term xe2x80x9cacyl groupxe2x80x9d is to be interpreted in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulphonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and, above all, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl or butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (xe2x80x9ccarbobenzoxyxe2x80x9d), 4-methoxybenzyloxycarbonyl, FMOC; arylsulphonyl such as Mtr. Preferred amino-protective groups are BOC and Mtr, and furthermore CBZ, Fmoc, benzyl and acetyl.
The term xe2x80x9chydroxyl-protective groupxe2x80x9d is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out at other sites of the molecule. Typical such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore also alkyl groups. The nature and the size of the hydroxyl-protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms are preferred. Examples of hydroxyl-protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulphonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is effectedxe2x80x94depending on the protective group usedxe2x80x94for example with strong acids, expediently with TFA or perchloric acid, but also with other strong inorganic acids, such as hydrochloric acid or sulphuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulphonic acids, such as benzene- or p-toluenesulphonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, or furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are furthermore possible. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is used in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperatures for the cleavage are expediently between about 0 and about 50xc2x0, and the reaction is preferably carried out at between 15 and 30xc2x0 (room temperature).
The groups BOC, OBut and Mtr can preferably be cleaved off, for example, with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30xc2x0, and the FMOC group can be cleaved off with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30xc2x0.
Protective groups which can be removed by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst, such as palladium, expediently on a support, such as carbon). Suitable solvents for this reaction are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100xc2x0 under pressures between about 1 and 200 bar, preferably at 20-30xc2x0 and 1-10 bar. Hydrogenolysis of the CBZ group is effected readily, for example, on 5-10% Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30xc2x0.
Compounds of the formula I
in which
R1 is
X is xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94COxe2x80x94,
and R2, R3 and Y are as defined in Claim 1,
can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
In the compounds of the formula III, L is preferably Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulphonyloxy having 1-6 C atoms (preferably methylsulphonyloxy), or arylsulphonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulphonyloxy).
The reaction is generally carried out in an inert solvent, in the presence of an acid binder, preferably an alkali metal hydroxide, carbonate or bicarbonate or an alkaline earth metal hydroxide, carbonate or bicarbonate, or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amine component of the formula II or of the alkylation derivative of the formula III may also be favourable. Depending on the conditions used, the reaction time is between several minutes and 14 days, the reaction temperature is between approximately 0xc2x0 and 150xc2x0, usually between 20xc2x0 and 130xc2x0.
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetra-chloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitrites, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); carbon disulphide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the solvents mentioned.
The starting materials of the formulae II and III are generally known. Those which are novel, however, can be prepared by methods known per se.
Compounds of the formula I
in which
R1 is
Y is SO2, CO or COO,
and R2 and X are as defined in Claim 1,
can preferably be obtained by reacting compounds of the formula IV with compounds of the formula V.
In the compounds of the formula IV L is preferably Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulphonyloxy having 1-6 C atoms (preferably methylsulphonyloxy), or arylsulphonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulphonyloxy).
The reaction of the compounds of the formula IV with compounds of the formula V is preferably carried out in an inert solvent, with addition of a base and at temperatures as indicated above.
The starting materials of the formulae IV and V are generally known. Those which are novel, however, can be prepared by methods known per se.
Compounds of the formula I
in which
R1 is
Y is CONH,
and R2 and X are as defined in Claim 1,
can preferably be obtained by reacting compounds of the formula VI with compounds of the formula V.
The reaction of the compounds of the formula VI with compounds of the formula V is preferably carried out in an inert solvent and at temperatures as indicated above.
The starting materials of the formula VI are generally known. Those which are novel, however, can be prepared by methods which are known per se.
Compounds of the formula I in which R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NF2 can furthermore be obtained from the corresponding cyano compound.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxamidine with hydrogen in the presence of a catalyst, such as, for example, Pd/C.
To prepare an amidine of he formula I (R1xe2x95x90xe2x80x94C(xe2x95x90NH)xe2x80x94NH2), ammonia can also be added onto a nitrile of the formula I (R1xe2x95x90CN). The addition is preferably carried out in several stages by a procedure in which, in a manner known per se, a) the nitrile is converted with H2S into a thioamide, which is converted with an alkylating agent, for example CH3I, into the corresponding S-alkyl-imidothioester, which in turn reacts with NF3 to give the amidine, b) the nitrile is converted with an alcohol, for example ethanol, in the presence of HCl into the corresponding imidoester, and this is treated with ammonia, or c) the nitrile is reacted with lithium bis(trimethylsilyl)amide and the product is then hydrolysed.
Furthermore, it is possible to convert a compound of the formula I into another compound of the formula I by converting one or more radicals R1, R2 R3 R4 and/or R5 into one or more radicals R11 R2, R3, R4 and/or R5, for example by reducing nitro groups (for example by hydrogenation over Raney nickel or Pd/carbon in an inert solvent, such as methanol or ethanol) to amino groups.
Esters can be hydrolysed, for example with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100xc2x0.
It is furthermore possible to acylate free amino groups in a customary manner with an acyl chloride or acid anhydride or to alkylate with an unsubstituted or substituted alkyl halide, expediently in an inert solvent, such as dichloromethane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between xe2x88x9260 and +30xc2x0.
A base of the formula I can be converted into the associated acid addition salt with an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, and subsequent evaporation. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus, it is possible to use inorganic acids, for example sulphuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulphaminic acid, or furthermore organic acids, in particular aliohatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulphonic or sulphuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, naphthalene-mono- or -disulphonic acids and lauryl-sulphuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted with bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal salts or into the corresponding ammonium salts.
Owing to their molecular structure, the compounds of the formula I according to the invention can be chiral and can consequently be present in various enantiomeric forms. They may therefore be present in racemic or in optically active form.
Since the pharmaceutical activity of the racemates and/or the stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates may be separated into enantiomeric compounds using chemical or physical means known to the person skilled in the art, or they may even be employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids, such as the R- and S-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulphonylproline) or the various optically active camphorsulphonic acids. A chromatographic separation of the enantiomers can also be advantageously carried out with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Solvents which are suitable for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.
The invention furthermore provides the use of the compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by a non-chemical route. For this purpose, they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid carrier or auxiliary, and if appropriate in combination with one or more further active compounds.
The invention furthermore provides pharmaceutical formulations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These formulations can be used as medicaments in human or veterinary medicine. Possible carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical administration. The novel compounds can also be lyophilized and the resulting lyophilisates can be used, for example, for the preparation of injection formulations. The formulations mentioned can be sterilized and/or comprise auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavourings and/or several further active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be employed for combating and preventing thromboembolic disorders, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens. For this purpose, the substances according to the invention are usually preferably administered in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, diet, on the administration time and route, and on the rate of excretion, medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.
All temperatures hereinabove and hereinbelow are given in xc2x0 C. In the following examples, xe2x80x9ccustomary work-upxe2x80x9d means: water is added, if necessary, the pH is brought to values of between 2 and 10, if necessary, depending on the structure of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulphate and evaporated and the residue is purified by chromatography over silica gel and/or crystallization. Rf values are for silica gel; mobile phase: ethyl acetate/methanol 9:1.
Mass spectrometry (MS):
EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+

Benzamidine derivatives as factor XA inhibitors

Abstract: Novel compounds of the formula I

Abstract: in which

Abstract: X, Y, R1, R2 and R3 are as defined in Patent Claim 1

Abstract: are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic disorders.


According to an aspect of the present invention there is provided an LSI device having an output terminal outputting a data, comprising a data output circuit connected to the output terminal and capable of adjusting an output impedance thereof; and an adjustment circuit which detects a transient voltage at the output terminal when an output logic of the data output circuit is switched in a condition that a transmission line not terminated by a terminating resistor is connected to the output terminal, compares the transient voltage with a reference voltage, and adjusts the output impedance of the data output circuit so as to match a characteristic impedance of the transmission line. According to the present invention, as the transient voltage of the output terminal connected to the transmission line is detected, and the output impedance of the data output circuit is adjusted, it is possible to adjust so that output impedance of the data output circuit is matched with characteristic impedance of the transmission line even if manufacture processes, use temperatures, power supply voltages, characteristic impedance of the transmission line, or the like fluctuates or is changed.

1. Field of the Invention
The present invention relates generally to an LSI device, and more particularly, to an LSI device capable of adjusting the output impedance so as to match the characteristic impedance of a transmission line irrespective of the variance of use environments such as temperatures and power supply voltages.
2. Description of the Related Arts
The LSI device outputs a processed signal from a data output circuit in the LSI device to a transmission line. In this case, it is desirable that output impedance of the data output circuit is matched with characteristic impedance of the transmission line. This is because, if the data output circuit is matched with the impedance of the transmission line, a reflection of a signal at a connection point of the both disappears, and it is possible to prevent damping of the signal to be transmitted to the transmission line.
For this reason, in the conventional LSI device, a simulation of the connection of the data output circuit with the transmission line is made to determine an output transistor size of the data output circuit, or the data output circuit is connected actually with the transmission line to observe a signal waveform, and the transistor size of the data output circuit is trimmed, so that the output impedance is matched to the characteristic impedance of the transmission line.
However, if the output transistor size of the data output circuit is fixed by trimming, when a manufacture process fluctuates, or when fluctuations such as temperatures, power supply voltages, characteristic impedance of the transmission line, or the like generate in the case where the LSI device is used, the output impedance of the data output circuit is not matched with the characteristic impedance of the transmission line.
Furthermore, after the LSI device is manufactured, in the case where a user""s use conditions in use temperatures, power supply voltages, characteristic impedance of the transmission line, or the like are changed, it is impossible to agree the output impedance with the user""s use conditions by changing the output transistor size of the data output circuit.
It is therefore the an object of the present invention to provide an LSI device which can be adjusted so that output impedance of a data output circuit is matched with characteristic impedance of a transmission line even if manufacture processes, use temperatures, power supply voltages, characteristic impedance of the transmission line, or the like fluctuates or is changed.
In order to achieve the above object, according to an aspect of the present invention there is provided an LSI device having an output terminal outputting a data, comprising a data output circuit connected to the output terminal and capable of adjusting an output impedance thereof; and an adjustment circuit which detects a transient voltage at the output terminal when an output logic of the data output circuit is switched in a condition that a transmission line not terminated by a terminating resistor is connected to the output terminal, compares the transient voltage with a reference voltage, and adjusts the output impedance of the data output circuit so as to match a characteristic impedance of the transmission line.
According to the present invention, as the transient voltage of the output terminal connected to the transmission line is detected, and the output impedance of the data output circuit is adjusted, it is possible to adjust so that output impedance of the data output circuit is matched with characteristic impedance of the transmission line even if manufacture processes, use temperatures, power supply voltages, characteristic impedance of the transmission line, or the like fluctuates or is changed.
In order to achieve the above object, according to another aspect of the present invention there is provided an LSI device having an output terminal outputting a data, a dummy output terminal outputting a dummy data, and a dummy input terminal which accepts the dummy data through a dummy transmission line, the LSI device comprising a data output circuit connected to the output terminal and capable of adjusting an output impedance thereof; a dummy output circuit connected to the dummy output terminal and having a configuration equivalent to that of the data output circuit; and an adjustment circuit which detects a transient voltage at the dummy output terminal when an output logic of the dummy data output circuit is switched in a condition that a dummy transmission line is connected between the dummy output terminal and the dummy input terminal, compares the transient voltage with a reference voltage, and adjusts the output impedance of the data output circuit and of the dummy output circuit so as to match a characteristic impedance of the dummy transmission line.
According to the present invention, as the transient voltage of the dummy output terminal connected to the dummy transmission line is detected to adjust the output impedance of the dummy output circuit and data output circuit, even if manufacture processes, use temperatures, power supply voltages, characteristic impedance of the transmission line, or the like fluctuates or is changed, the output impedance of the data output circuit can be adjusted so as to match the characteristic impedance of the transmission line.
Preferably, the transient voltage is detected at the timing when a logic of a signal fed to the dummy input terminal is switched, and the transient voltage is a voltage substantially intermediate of the amplitude of the signal.
According to the present invention, as the transient voltage can be detected at the timing that the logic of the signal to be input into the dummy input terminal is switched, it is possible to readily detect a substantially intermediate voltage of the signal amplitude.

LSI device capable of adjusting the output impedance to match the characteristic impedance


A method for processing a handoff in a mobile communication terminal. If a handoff direction message received from a base station is a hard handoff direction message, the mobile communication terminal transmits an acknowledgement message to the base station in response to the handoff direction message and then performs a hard handoff. If the handoff direction message received from the base station is a soft handoff direction message, the mobile communication terminal performs a soft handoff, incorporates an acknowledgement message into a soft handoff completion message when the soft handoff is completed, and transmits the soft handoff completion message containing the acknowledgement message to the base station.

1. Field of the Invention
The present invention relates to a method for processing a handoff in a mobile communication system, and more particularly to a method for processing a handoff in a mobile communication terminal.
2. Description of the Related Art
Conventionally, the term "handoff" means a function for continuing a call by automatically coupling a mobile communication terminal from a traffic channel of a radio cell to another traffic channel of another radio cell when a subscriber of the mobile communication terminal moves from the radio cell to another radio cell.
In a mobile communication system based on a CDMA (Code Division Multiple Access), the handoff is divided into a hard handoff, a soft handoff, and a softer handoff. The hard handoff is performed when the mobile communication terminal moves between base stations using different frequencies. In this case, an instantaneous call cutoff can occur in a call connection state, but the call can be coupled to another base station next to a corresponding base station so quickly that a caller does not experience any inconvenience during communicating with a called party. The soft handoff is performed when the mobile communication terminal moves between base stations using a same frequency. Because the mobile communication terminal moving between the base stations uses the same frequency in the soft handoff, it does not affect the call. The softer handoff is performed when the mobile communication terminal moves between sectors located within one radio cell being covered by a base station. The procedure of processing the softer handoff is similar to the procedure of processing the soft handoff.
The handoffs described above are performed between the base stations and the mobile communication terminal. A procedure of transmitting and receiving messages in a conventional handoff will be described with reference to FIG. 1. FIG. 1 is a flow chart illustrating an operation of the mobile communication terminal according to a conventional handoff process. First, the mobile communication terminal transmits a pilot strength measurement message to a base station to which the mobile communication terminal belongs in step 101. In response to the pilot strength measurement message, the base station transmits a handoff direction message to the mobile communication terminal. The mobile communication terminal receives the handoff direction message from the base station in step 103. In response to the handoff direction message, the mobile communication terminal always transmits an acknowledgement message to the base station in step 105. The mobile communication terminal is coupled to a new base station or its traffic channel to perform the handoff in step 107. The mobile communication terminal transmits a handoff completion message to the base station in step 109 and then the handoff ends.
As an improvement of an initial handoff, the conventional handoff as the FIG. 1 has improved the initial handoff by carrying the acknowledgement message with the handoff completion message after the mobile communication terminal receives the handoff direction message.
The above-described, conventional handoff may have some degree of merit in view of power saving when used in a soft handoff, but it has a drawback of having frequent call drops when used in a hard handoff, because after Tx is disabled to make a frequency change and then enabled to a new frequency, in case of the hard handoff, the call drop is frequently caused when transmitting a handoff completion message (HCM), mostly due to differences in system design rules.
The conventional procedure of processing the handoff as illustrated in FIG. 1 reduces a call drop rate when the hard handoff is performed, but does not work perfectly, due to differences in the system design rules. In addition, there is a problem in that the conventional procedure can cause unnecessary power consumption and over load by unconditionally transmitting an acknowledgement message when the soft handoff is performed.
Further, a so-called Fast Acknowledgement system, which was first adopted in an IS-2000 system, has introduced an improved system of transmitting an acknowledgement message immediately in an Rx/Tx (Reception/Transmission) (Layer 2) task after a mobile terminal has received a handoff Direction Message (HDM). This Fast Acknowledgement system may efficiently eliminate such call drop phenomena by disabling Tx before transmitting of an Acknowledgement message to a base station in the hard handoff in between frequencies, the Acknowledgement message being sent from a Main Control (MC) (Layer 3) task. However, the Fast Acknowledgement system still has some disadvantages in view of a power saving and overhead, because the Acknowledgement message is unconditionally transmitted irrespective of whether the Acknowledgement message from the Rx/Tx task is soft handoff or hard handoff, and no validation to the message is performed.

Method for processing a handoff in a mobile communication terminal


A magnetic ring adapted to be worn on the little finger of the hand. The magnetic ring includes a ring and a pair of permanent magnets that extend from the ring. When the magnetic ring is worn on the little finger of the right hand, the pair of permanent magnets are oriented on the top and bottom, respectively, of the little finger, with the South pole of the magnet that is oriented on the top of the little finger generally contacting the top of the little finger, with the North pole of the magnet that is oriented on the top of the little finger in opposition thereto, with the North pole of the magnet that is oriented on the bottom of the little finger generally contacting the bottom of the little finger, and with the South pole of the magnet that is oriented on the bottom of the little finger in opposition thereto. When the magnetic ring is worn on the little finger of the left hand, the position of the polarities of the pair of permanent magnets are reversed from that of the right hand. The magnetic ring can also be made to fit around all the fingers of the hand and all the toes of the foot.

1. Field of the Invention
The present invention relates to a ring. More particularly, the present invention relates to a magnetic ring.
2. Description of the Prior Art
The whole human body is a magnetic community. Each individual cell is a magnet and has polarities of North and South just like a regular magnet. That is why cells attract each other and form finally into a more complicated community, an animal body.
As shown in FIG. 1, a human body carries magnetic flux current which cycles around the body. If this magnetic flux cycle in the body gets stronger, and faster, the healthier the body should become. The reason why a person gets healthier if his magnetic flux becomes stronger or faster is because blood circulation is directly proportional to magnetic flux. The body circulates blood with its natural turbine, magnet flux, which consists of no moving parts but yet still propels blood into a circulating system.
Numerous innovations for magnetic jewelry have been provided in the prior art that will be described. Even though these innovations may be suitable for the specific individual purposes to which they address, however, they differ from the present invention.
FOR EXAMPLE, U.S. Pat. No. 3,835,664 to Nesbit teaches means for reducing the diameter of a finger ring to produce a fit secure and comfortable for the wearer. The ring is fitted with a relatively flat member directly beneath the setting facing inwardly of the ring. This member may be constructed of a magnetic material or may be of a material such as iron which is attracted to a magnet. The member is secured by means of a suitable adhesive or by soldering or the like. In order to reduce the diameter size of the ring, a disc-like shim, which may be a magnet, is positioned on the underside of the secured member. The shim, is not adhesively secured but is secured to the member by magnetic attraction so that if the member is a magnet, the shim need not be, but can be of an attractable material. Shims of varying sizes may be employed so that the diameter of the ring may be modified over considerable reductions.
ANOTHER EXAMPLE, U.S. Pat. No. 4,095,587 to Ishikawa teaches a magnetic ornament, such as a bracelet, a necklace or a chain belt, suitable for promoting good health and personal adornment. The magnetic ornament is comprised of at least one capsule linked with at least one chain. The capsule has enclosed therein one or more pieces of a rare earth-cobalt permanent magnet having the magnetic poles formed on the peripheral surface. At least the surfaces of the capsule and the chain are made of non-magnet corrosion-resistant metal.
STILL ANOTHER EXAMPLE, U.S. Pat. No. 4,186,567 to Monden et al. teaches an ornament adapted to be fixed by permanent magnets and has an ornament piece to which is fixed a gem or the like, and an attracting piece confronting the ornament piece. The ornament piece and/or the attracting piece is provided with a rare earth-cobalt magnet embedded therein, so that these pieces may be held by each other by means of the magnetic attracting force which acts across a non-magnetic body such as an earlobe. The level of the magnetic attracting force is so selected as to fall, when the pieces confront each other across a distance approximately the thickness of an ear lobe, within a range of between 30 grams and 100 grams per square centimeter of attaching area and, at the same time, to be larger than 30 grams per gram of weight of the ornament, so that the user may put on the ornament which may be an earring, without pain nor the fear of unintentional dropping.
YET ANOTHER EXAMPLE, U.S. Pat. No. 4,912,944 to Crosley et al. teaches an article of jewelry comprising a base element which supports an ornamented substrate element thereon by magnetic attraction, both the base element and the substrate element having magnetically attractable properties and at least one of them having the properties of a permanent magnet, whereby the substrate element is interchangeable with other like elements bearing different ornamentation.
FINALLY, STILL YET ANOTHER EXAMPLE, U.S. Pat. No. 5,349,725 to Levy teaches a jewelry closure that includes a magnetic closure and a mechanical closure which is a safety feature, preventing the magnetic closure from being opened inadvertently. A plate-like mechanical closure member attached to one of the magnetic closure members engages a complementarily shaped portion of the other magnetic closure member when the magnetic closure is secured to provide a mechanical second closure for the jewelry. The combined magnetic and mechanical jewelry closure may be used to close chains. The closure may also be disposed on a hinged ring. The ring may be used for passing through ends of a decorative chain as a closure for the chain. The closure may also be used on a hinged ring for wearing on a finger and is particularly useful if the finger joints are swollen. Other uses include adaptation for a hinged charm for closing a chain or for adding to a chain.
It is apparent that numerous innovations for magnetic jewelry have been provided in the prior art that are adapted to be used. Furthermore, even though these innovations may be suitable for the specific individual purposes to which they address, however, they would not be suitable for the purposes of the present invention as heretofore described.


A non-directional signal combiner including a common ground plane, first and second coaxial cable connectors and a sum port. Each of the connectors has an inner conductor and an outer conductor, with the outer conductors connected to the common ground plane. The combiner also includes first and second coaxial cables, each having inner and outer conductors. The inner conductor of the first coaxial cable extends between the inner conductor of the first connector and the sum port, while the inner conductor of the second coaxial cable extends between the inner conductor of the second connector and the sum port. Each of the first and the second coaxial cables are wound into coils.

The development of solid-state power amplifiers for RF transmitters has created challenges to designers not present in previous tube designs. One major problem with solid-state designs is their limited power handling capability. While high power devices have been developed, they are generally quite expensive and thus are not desirable for designs where cost is a significant factor.
One strategy for solving this dilemma has been to divide the signal to be amplified into several components and direct them to a like number of smaller solid-state power amplifiers. The outputs of the power amplifiers are then combined to provide an output signal level which is comparable to or higher than the output signal which could have been obtained from a single high power solid-state power amplifier.
This divide-and-conquer strategy has its own drawbacks, however. The primary drawback was that previous signal dividers and combiners had used conventional wound transformers and lumped inductive and capacitive components to achieve the required impedance matching. Such components are inherently narrow-banded and are thus impractical for applications where wide bandwidths are required. Modern solid-state power amplifiers are generally broad-banded, and conventional narrow-banded signal dividers and combiners severely limited their utility.
One solution to such narrow-banded dividers and combiner was provided by U.S. Pat. No. 4,774,481 to Edwards et al., which discloses a broadband non-directional signal combiner (non-directional meaning that the combiner can be used as either a combiner or a divider). The combiner utilizes coaxial cables interconnected in a bridge configuration, and a coaxial cable transformer. The bridge configuration increases bandwidth, while the transformer counteracts the impedance transforming characteristics of the combiner. The combiner disclosed by Edwards et al. also incorporated ferrite sleeves over each coaxial cable in the combiner to eliminate even mode impedances between the cable outer conductors and the common ground plane.
The resulting combiner disclosed by Edwards et al. combines and divides signals across a broad range of frequencies with relatively large isolation between input ports, and a low voltage standing wave ratio. However, the use of ferrite sleeves introduces core losses resulting in heat dissipation and degraded intermodulation distortion performance ("IMD") at high power levels, limiting its usefulness in some applications. In addition, the combiner has a relatively large number of interconnections which act as discontinuities in the circuit, which increase insertion losses.
What is still needed, therefore, is a non-directional signal combiner having a short signal path with few discontinuities, such that insertion losses are low and relatively little inductance is required in the signal path. What is also needed is a non-directional combiner that combines and divides signals across a broad range of frequencies with large isolation between input ports and a low voltage standing wave ratio. What is further needed is a non-directional combiner that inherently exhibits excellent IMD characteristics, such that high power can be handled with little distortion. Preferably, the combiner will also have a simple design, be conducive to mass production, and be rugged and durable yet relatively inexpensive.

High power broadband non-directional combiner


Attenuated respiratory syncytial virus (RSV) and vaccine compositions thereof are produced by introducing specific mutations associated with attenuating phenotypes into wild-type or RSV which is incompletely attenuated by cold-passage or introduction of mutations which produce virus having a temperature sensitive (ts) or cold adapted (ca) phenotype. Alternatively, recombinant RSV and vaccine compositions thereof incorporate attenuating and other mutations specifying desired structural and or phenotypic characteristics in an infectious RSV. Recombinant RSV incorporate desired mutations specified by insertion, deletion, substitution or rearrangement of a selected nucleotide sequence, gene, or gene segment in an infectious RSV clone. The immune system of an individual is stimulated to induce protection against natural RSV infection, or multivalently against infection by RSV and another pathogen, such as PIV, by administration of attenuated, biologically derived or recombinant RSV.

Human respiratory syncytial virus (RSV) outranks all other microbial pathogens as a cause of pneumonia and bronchiolitis in infants under one year of age. Virtually all children are infected by two years of age, and reinfection occurs with appreciable frequency in older children and young adults (Chanock et al., in Viral Infections of Humans, 3rd ed., A. S. Evans, ed., Plenum Press, N.Y. (1989)). RSV is responsible for more than one in five pediatric hospital admissions due to respiratory tract disease, and causes an estimated 91,000 hospitalizations and 4,500 deaths yearly in the United States alone. Although most healthy adults do not have serious disease due to RSV infection, elderly patients and immunocompromised individuals often suffer severe and possibly life-threatening infections from this pathogen.
Despite decades of investigation to develop effective vaccine agents against RSV, no safe and effective vaccine has yet been achieved to prevent the severe morbidity and significant mortality associated with RSV infection. Failure to develop successful vaccines relates in part to the fact that small infants have diminished serum and secretory antibody responses to RSV antigens. Thus, these individuals suffer more severe infections from RSV, whereas cumulative immunity appears to protect older children and adults against more serious impacts of the virus. One antiviral compound, ribavarin, has shown promise in the treatment of severely infected infants, although there is no indication that it shortens the duration of hospitalization or diminishes the infant's need for supportive therapy.
The mechanisms of immunity in RSV infection have recently come into focus. Secretory antibodies appear to be most important in protecting the upper respiratory tract, whereas high levels of serum antibodies are thought to have a major role in resistance to RSV infection in the lower respiratory tract. Purified human immunoglobulin containing a high titer of neutralizing antibodies to RSV may prove useful in some instances of immunotherapeutic approaches for serious lower respiratory tract disease in infants and young children. Immune globulin preparations, however, suffer from several disadvantages, such as the possibility of transmitting blood-borne viruses and difficulty and expense in preparation and storage.
Formalin-inactivated virus vaccine was tested against RSV in the mid-1960s, but failed to protect against RSV infection or disease, and in fact exacerbated symptoms during subsequent infection by the virus. (Kim et al., Am. J. Epidemiol., 89:422-434 (1969), Chin et al., Am J. Epidemiol., 89:449-463 (1969); Kapikian et al., Am. J. Epidemiol., 89:405-421 (1969)).
More recently, vaccine development for RSV has focused on attenuated RSV mutants. Friedewald et al., J. Amer. Med. Assoc. 204:690-694 (1968) reported a cold passaged mutant of RSV (cpRSV) which appeared to be sufficiently attenuated to be a candidate vaccine. This mutant exhibited a slight increased efficiency of growth at 26° C. compared to its wild-type parental virus, but its replication was neither temperature sensitive nor significantly cold-adapted. The cold-passaged mutant, however, was attenuated for adults. Although satisfactorily attenuated and immunogenic for infants and children who had been previously infected with RSV (i.e., seropositive individuals), the cpRSV mutant retained a low level virulence for the upper respiratory tract of seronegative infants.
Similarly, Gharpure et al., J. Virol. 3:414-421 (1969) reported the isolation of temperature sensitive RSV (tsRSV) mutants which also were promising vaccine candidates. One mutant, ts-1, was evaluated extensively in the laboratory and in volunteers. The mutant produced asymptomatic infection in adult volunteers and conferred resistance to challenge with wild-type virus 45 days after immunization. Again, while seropositive infants and children underwent asymptomatic infection, seronegative infants developed signs of rhinitis and other mild symptoms. Furthermore, instability of the ts phenotype was detected, although virus exhibiting a partial or complete loss of temperature sensitivity represented a small proportion of virus recoverable from vaccinees, and was not associated with signs of disease other than mild rhinitis.
These and other studies revealed that certain cold-passaged and temperature sensitive RSV strains were underattenuated and caused mild symptoms of disease in some vaccinees, particularly seronegative infants, while others were overattenuated and failed to replicate sufficiently to elicit a protective immune response, (Wright et al., Infect. Immun., 37:397-400 (1982)). Moreover, genetic instability of candidate vaccine mutants has resulted in loss of their temperature-sensitive phenotype, further hindering development of effective RSV vaccines. See generally, Hodes et al., Proc. Soc. Exp. Biol. Med. 145:1158-1164 (1974), McIntosh et al., Pediatr. Res. 8:689-696 (1974), and Belshe et al., J. Med. Virol., 3:101-110 (1978).
Abandoning the attenuated RS virus vaccine approach, investigators tested potential subunit vaccine candidates using purified RS virus envelope glycoproteins from lysates of infected cells. The glycoproteins induced resistance to RS virus infection in the lungs of cotton rats, Walsh et al., J. Infect. Dis. 155:1198-1204 (1987), but the antibodies had very weak neutralizing activity and immunization of rodents with purified subunit vaccine led to disease potentiation (Murphy et al., Vaccine 8:497-502 (1990)).
Vaccinia virus recombinant-based vaccines which express the F or G envelope glycoprotein have also been explored. These recombinants express RSV glycoproteins which are indistinguishable from the authentic viral counterpart, and small rodents infected intradermally with the vaccinia-RSV F and G recombinant viruses developed high levels of specific antibodies that neutralized viral infectivity. Indeed, infection of cotton rats with vaccinia-F recombinants stimulated almost complete resistance to replication of RSV in the lower respiratory tract and significant resistance in the upper tract. Olmsted et al., Proc. Natl. Acad. Sci. USA 83:7462-7466 (1986). However, immunization of chimpanzees with vaccinia F and vaccinia G recombinant provided almost no protection against RSV challenge in the upper respiratory tract (Collins et al., Vaccine 8:164-168 (1990)) and inconsistent protection in the lower respiratory tract (Crowe et al., Vaccine 11:1395-1404 (1993).
The unfulfilled promises of attenuated RSV strains, subunit vaccines, and other strategies for RSV vaccine development underscores a need for new methods to identify genetic targets for recombinant engineering of novel RSV vaccines, and to develop methods for manipulating recombinant RSV to incorporate genetic changes to yield new phenotypic properties in viable, attenuated RSV recombinants. However, manipulation of the genomic RNA of RSV and other negative-sense RNA viruses has heretofore proven difficult. Major obstacles in this regard include non-infectivity of naked genomic RNA of these viruses, poor viral growth in tissue culture, lengthy replication cycles, virion instability, a complex genome, and a refractory organization of gene products.
Methods for direct genetic manipulation of nonsegmented, negative stranded RNA viruses have only recently begun to be developed (for reviews, see Conzelmann, J. Gen. Virol. 77:381-89 (1996); Palese et al., Proc. Natl. Acad. Sci. U.S.A. 93:11354-58, (1996)). Successful rescue has been achieved for infectious rabies virus, vesicular stomatitis virus (VSV), measles virus, and Sendai virus from cDNA-encoded antigenomic RNA in the presence of the nucleocapsid N, phosphoprotein P, and large polymerase subunit L (Garcin et al., EMBO J. 14:6087-6094 (1995); Lawson et al., Proc. Natl. Acad. Sci. U.S.A. 92:4477-81 (1995); Radecke et al., EMBO J. 14:5773-5784 (1995); Schnell et al., EMBO J. 13:4195-203 (1994); Whelan et al., Proc. Natl. Acad. Sci. U.S.A. 92:8388-92 (1995)). Successful rescue of RSV also requires an additional protein, the M2 ORF1 transcriptional elongation factor (Collins et al., Proc. Natl. Acad. Sci. USA 92:11563-7 (1995)).
Rescue of infectious RSV has been complicated by a number of factors. Specifically, RSV possesses several properties which distinguish it and other members of the genus Pneumovirus from better characterized paramyxoviruses of the genera Paramyxovirus, Rubulavirus and Morbillivirus. These differences include a greater number of mRNAs, an unusual gene order at the 3′ end of the genome, species-to-species variability in the order of the glycoprotein and M2 genes, a greater diversity in intergenic regions, an attachment protein that exhibits mucin-like characteristics, extensive strain-to-strain sequence diversity, and several proteins not found in other nonsegmented negative stranded RNA viruses.
In view of the foregoing, an urgent need exists in the art for tools and methods to engineer safe and effective vaccines to alleviate the serious health problems attributable to RSV, particularly illnesses among infants and children. Quite surprisingly, the present invention satisfies these and other related needs.

This patent is subject to a terminal disclaimer.

Production of attenuated respiratory syncytial virus vaccines from cloned nucleotide sequences

The United States of America as represented by the Department of Health and Human Services


Systems, devices, and methods are provided for updating information resident on an avionics device. One avionics device embodiment includes a processor, a memory, and a receiver. The memory can be in communication with the processor. The receiver can receive radio signals including update information. The device can update information resident on the device based upon the update information received.

Electronic devices and systems are playing an ever increasing role in the field of avionics. For instance, the use of Global Positioning System (GPS) technology coupled with electronic navigational maps allows a pilot of an aircraft to chart the location and course of the aircraft.
Electronic devices can allow the pilot to navigate the aircraft by viewing the information displayed on a monitor, for example on a cockpit instrument panel, or the like. Cockpit instrument panels can include for example, a single device that is capable of providing the above functions, an integrated group of devices for providing the functions, or separate devices all providing functions independently.
Some devices can be utilized to indicate, the location of airports, waypoints, obstacles, and the like en route. Devices can also provide capabilities such as aircraft attitude, altitude, engine instrumentation, weather link data, and traffic and terrain data, among other functions. The devices that provide the functionality in the cockpit are increasingly utilizing software to provide various functions.
However, once installed in an aircraft, the application and operating system software that provides the functionality to the cockpit cannot typically be updated without a hardwired connection between the computer system of the aircraft and a server having the updates. Therefore, in order to update the software, the computer either has to be removed from the aircraft or a wired connection has to be made with the computer.
Some proposed systems are capable of being updated through use of a close proximity transfer mechanism such as Bluetooth, 802.11 (wi-fi), or Infrared technologies. However, these methods require the use of a device, having the updates thereon, that is in close proximity to the avionics computer on the aircraft. These devices typically are portable in order for the device to get close enough to make the connection to the computer on the aircraft. However, these systems are not suitable in all situations.
For example, when the size of the update is too large to be held on a portable device, the portable device would not be effective to execute updates. Additionally, in order to update the computer systems on a number of aircraft, the portable device would have to be brought into proximity to each aircraft. Such devices may not be readily available to all aircraft. For these and other reasons, this method of updating may not be accessible.

Delivering data updates to an avionics device


An adjustment tool for adjusting a maneuvering mechanism of a main landing gear of an aircraft, the landing gear having a plurality of wheels. The tool includes a telemeter, a locking system for locking the telemeter on the external face of a wheel, a wireless communication unit that is connected to the telemeter and makes it possible, when the tool is being used, to connect the telemeter with a control device provided with a display screen.

With reference to FIG. 1, a main landing gear 1 of an aircraft comprises a landing gear strut 2 that is fastened inside a landing gear bay 3 of the aircraft and mounted so as to be able to pivot on the aircraft about a pivot axis that is parallel to the longitudinal axis X of the fuselage of the aircraft, a bogie rocker arm 4 that is fastened to the end of the landing gear strut 2 and extends parallel to the longitudinal axis X, and axles 5 that are mounted on the bogie rocker arm 4 and on which are mounted wheels 6 that are all identical. The landing gear 1 also comprises a maneuvering mechanism 7, for example with actuators, for moving the landing gear between an extended position in which the landing gear strut 2 is substantially perpendicular to the longitudinal axis X of the aircraft, and a retracted position in which the landing gear 1 is entirely folded into the bay 3. In the extended and retracted positions, doors 8 close the landing gear bay 3 in order to reduce the drag that affects the aircraft.
The maneuvering mechanism 7 has to be adjusted so as to leave a space E between the doors 8 and the main landing gear 1 that is sufficient for the doors 8 to be able to be closed without the risk of contact with the main landing gear 1 after the latter has reached its retracted position.
In order to carry out the adjustments, the aircraft is mounted on props and the maneuvering mechanism 7 is activated so as to move the main landing gear 1 from its extended position to its retracted position. An operator positioned in the landing gear bay 3 measures the distance D between the top wall 3d (substantially horizontal surface) of the landing gear bay 3 and the main landing gear 1.
The operators adjust the maneuvering mechanism 7 so that, in the retracted position, the distance D between the top wall 3d (substantially horizontal surface) of the landing gear bay 3 and the main landing gear 1 is smaller than a predetermined value.

Tool for assisting with the adjustment of a maneuvering mechanism of a main landing gear


A vehicle 1 towing a trailer 4 is fitted with three video cameras 5, 6, 7 fitted to the rear of the vehicle and on each door mirror. A view from any camera can be presented to the driver on a display 11. A predicted trailer path, calculated in a computing unit 10, is also presented to the driver on the display 11 as guide lines overlaid on the camera view. The computing unit 10 is also configured to calculate a hitch angle by tracking the position of a trailer-mounted marker in the camera view.

It is known to equip vehicles with external video cameras for displaying to the driver an image of the surroundings in order to provide assistance with parking and reversing maneuvers. A track for a given steering angle can be superimposed on the displayed image including systems that display the view from a rearward-looking video camera onto a touch screen which is used to input a desired destination, such as a parking bay. Steering cues are also displayed on the screen for assisting the driver in the maneuvering operation.

Vehicle trailer angle detection system and method


An encapsulated magnet assembly has a magnet encapsulated during a two-step molding process. The first step includes molding a first molded section over a magnet assembly. The second step of the process includes molding a second molded section over the magnet and the first molded section in such a manner that the entire magnet is covered by the two molded sections completely. A first parting line is defined between the first and second molded sections along an elongate tapered section of the first molded section at the one end of the assembly. A second parting line is defined between the first and second molded sections at a dovetail on the first molded section. An outwardly tapered surface is provided on the dovetail. The two parting lines define leak-free seams between the two molded sections thereby sealingly encapsulating the magnet within the two molded sections.

The present invention relates in general to magnetic drive pumps, and in particular, to an encapsulated magnet for a magnetic drive pump and method of making the same.
A typical use for the present invention is in a pump having a magnetic drive. A magnetic drive pump has an outer annular magnet turned or rotated by a motor. An annular inner magnet is disposed within the outer magnet and is carried on a pump shaft. The inner magnet is isolated from the outer magnet by a thin metallic or plastic cup.
The inner magnet of such pumps includes a magnet and flux ring assembly which operates in the process fluid that is moved through a system by the pump. If the process fluid such as water contacts the assembly, the magnet and flux ring may corrode or rust. Additionally, the assignee of the present invention has researched using rare earth materials for the magnet for use in magnetic drive pumps. These rare earth materials are highly susceptible to corrosion when immersed in fluids such as water.
Several methods have been tried in order to correct the problem. One presently used method includes placing the magnet and flux ring inside a stainless-steel shell and molding an outer cover over the exposed assembly. Such a construction, disclosed in commonly assigned U.S. Pat. No. 4,414,523, is not adequate for all applications. Additionally, various coatings and platings have been applied to the magnet outer surface. Such methods and materials are not known to withstand contact with all process fluids and to maintain a leak-free encapsulation of the magnet.
One manufacturer, March Pump, has developed an over-molded vane pump using a two-step molding process for the magnet and impeller. The seam between the first molding step material and the second molding step material does not ensure a leak-free joint.

Encapsulated magnet for magnetic drive pumps


An oxidation catalyst is prepared by pyrolyzing a source of iron and a source of nitrogen on a carbon support. Preferably, a noble metal is deposited over the modified support which comprises iron and nitrogen bound to the carbon support. The catalyst is effective for oxidation reactions such as the oxidative cleavage of tertiary amines to produce secondary amines, especially the oxidation of N-(phosphonomethyl)iminodiacetic acid to N-(phosphonomethyl)glycine.

This invention is directed to redox reaction catalysts, and more particularly to improved catalysts effective for the reduction of molecular oxygen in the conduct of oxidation reactions. The invention more particularly relates to the preparation of secondary amines by catalytic oxidative cleavage of tertiary amines, e.g., the preparation of N-(phosphonomethyl)glycine by catalytic oxidation of N-(phosphonomethyl)iminodiacetic acid.
N-(phosphonomethyl)glycine (known in the agricultural chemical industry as "glyphosate") is described in Franz, U.S. Pat. No. 3,799,758. N-(phosphonomethyl)glycine and its salts are conveniently applied as a post-emergent herbicide in an aqueous formulation. It is a highly effective and commercially important broad-spectrum herbicide useful in killing or controlling the growth of a wide variety of plants, including germinating seeds, emerging seedlings, maturing and established woody and herbaceous vegetation, and aquatic plants.
Various methods for making N-(phosphonomethyl)glycine are known in the art. Franz, U.S. Pat. No. 3,950,402, teaches that N-(phosphonomethyl)glycine may be prepared by the liquid phase oxidative cleavage of N-(phosphonomethyl)iminodiacetic acid (sometimes referred to as "PMIDA") with oxygen in the presence of a catalyst comprising a noble metal deposited on the surface of an activated carbon support:
Other by-products also may form, such as formic acid, which is formed by the oxidation of the formaldehyde by-product; and aminomethylphosphonic acid, which is formed by the oxidation of N-(phosphonomethyl)glycine. Even though the Franz method produces an acceptable yield and purity of N-(phosphonomethyl)glycine, high losses of the costly noble metal into the reaction solution (i.e., "leaching") result because under the oxidation conditions of the reaction, some of the noble metal is oxidized into a more soluble form and both N-(phosphonomethyl)iminodiacetic acid and N-(phosphonomethyl)glycine act as ligands which solubilize the noble metal.
In U.S. Pat. No. 3,969,398, Hershman teaches that activated carbon alone, without the presence of a noble metal, may be used to effect the oxidative cleavage of N-(phosphonomethyl)iminodiacetic acid to form N-(phosphonomethyl)glycine. In U.S. Pat. No. 4,624,937, Chou further teaches that the activity of the carbon catalyst taught by Hershman may be increased by removing the oxides from the surface of the carbon catalyst before using it in the oxidation reaction. See also, U.S. Pat. No. 4,696,772, which provides a separate discussion by Chou regarding increasing the activity of the carbon catalyst by removing oxides from the surface of the carbon catalyst. Although these processes obviously do not suffer from noble metal leaching, they do tend to produce greater concentrations of formaldehyde by-product when used to effect the oxidative cleavage of N-(phosphonomethyl)iminodiacetic acid. This formaldehyde by-product is undesirable because it reacts with N-(phosphonomethyl)glycine to produce unwanted by-products (mainly N-methyl-N-(phosphonomethyl)glycine, sometimes referred to as "NMG") which reduce the N-(phosphonomethyl)glycine yield. In addition, the formaldehyde by-product itself is undesirable because of its potential toxicity. See Smith, U.S. Pat. No. 5,606,107.
Optimally, therefore, it has been suggested that the formaldehyde be simultaneously oxidized to carbon dioxide and water as the N-(phosphonomethyl)iminodiacetic acid is oxidized to N-(phosphonomethyl)glycine in a single reactor, thus giving the following reaction:
As the above teachings suggest, such a process requires the presence of both carbon (which primarily effects the oxidation of N-(phosphonomethyl)iminodiacetic acid to form N-(phosphonomethyl)glycine and formaldehyde) and a noble metal (which primarily effects the oxidation of formaldehyde to form carbon dioxide and water). Like Franz, Ramon et al. (U.S. Pat. No. 5,179,228) teach using a noble metal deposited on the surface of a carbon support. To reduce the problem of leaching (which Ramon et al. report to be as great as 30% noble metal loss per cycle), however, Ramon et al. teach flushing the reaction mixture with nitrogen under pressure after the oxidation reaction is completed to cause re-deposition of the noble metal onto the surface of the carbon support. According to Ramon et al., nitrogen flushing reduces the noble metal loss to less than 1%.
Using a different approach, Felthouse (U.S. Pat. No. 4,582,650) teaches using two catalysts: (i) an activated carbon to effect the oxidation of N-(phosphonomethyl)iminodiacetic acid into N-(phosphonomethyl)glycine, and (ii) a co-catalyst to concurrently effect the oxidation of formaldehyde to carbon dioxide and water. The co-catalyst consists of an aluminosilicate support having a noble metal located within its pores. The pores are sized to exclude N-(phosphonomethyl)glycine and thereby prevent the noble metal of the co-catalyst from being poisoned by N-(phosphonomethyl)glycine. According to Felthouse, use of these two catalysts together allows for the simultaneous oxidation of N-(phosphonomethyl)iminodiacetic acid to N-(phosphonomethyl)glycine and of formaldehyde to carbon dioxide and water. This approach, however, suffers from several disadvantages: (1) it is difficult to recover the costly noble metal from the aluminosilicate support for re-use; (2) it is difficult to design the two catalysts so that the rates between them are matched; and (3) the carbon support, which has no noble metal deposited on its surface, tends to deactivate at a rate which can exceed 10% per cycle.
Ebner et al., in U.S. Pat. No. 6,417,133, describe a deeply reduced noble metal on carbon catalyst which is characterized by a CO desorption of less than 1.2 mmole/g, preferably less than 0.5 mmole/g, when a dry sample of the catalyst, after being heated at a temperature of about 500° C. for about 1 hour in a hydrogen atmosphere and before being exposed to an oxidant following the heating in the hydrogen atmosphere, is heated in a helium atmosphere from about 20° to about 900° C. at a rate of about 10° C. per minute, and then at about 900° C. for about 30 minutes. The catalyst is further characterized as having a ratio of carbon atoms to oxygen atoms of at least about 20:1, preferably at least about 30:1, at the surface as measured by x-ray photoelectron spectroscopy after the catalyst is heated at a temperature of about 500° C. for about 1 hour in a hydrogen atmosphere and before the catalyst is exposed to an oxidant following the heating in the hydrogen atmosphere.
The catalysts of U.S. Pat. No. 6,417,133 have proven to be highly advantageous and effective catalysts for the oxidation of N-(phosphonomethyl)iminodiacetic acid to N-(phosphonomethyl)glycine, and for the further oxidation of by-product formaldehyde and formic acid, and without excessive leaching of noble metal from the carbon support. It has further been discovered that these catalysts are effective in the operation of a continuous process for the production of N-(phosphonomethyl)glycine by oxidation of N-(phosphonomethyl)iminodiacetic acid.
The advent of continuous processes for the oxidation of N-(phosphonomethyl)iminodiacetic acid has created an opportunity for further improvements in productivity through the development of catalysts which accelerate the rate of oxidation of N-(phosphonomethyl)iminodiacetic acid and/or formaldehyde beyond the rates achievable with the catalysts of U.S. Pat. No. 6,417,133. Since the productivity of a continuous oxidation reactor is not constrained by the turnaround cycle of a batch reactor, any improvement in reaction kinetics translates directly into an increase in the rate of product output per unit reactor volume.
Carbon and noble metal sites on the catalysts of U.S. Pat. No. 6,417,133 are highly effective for transfer of electrons in the oxidation of N-(phosphonomethyl)iminodiacetic acid, and the noble metal sites are especially effective for this purpose in the oxidation of formaldehyde and formic acid. However, the productivity of these reactions could be enhanced if the catalyst were more effective for transfer of electrons in the concomitant reduction of molecular oxygen, which can be a rate limiting step in the overall catalytic reaction between molecular oxygen and the N-(phosphonomethyl)iminodiacetic acid, formaldehyde, and formic acid substrates.