The present application claims priority under 35 U.S.C. xc2xa7 119 to German patent applications No. 19830430.7 filed Jul. 8, 1998, and No. 19903126.6 filed Jan. 27, 1999. Both priority applications are entirely incorporated herein by reference.
The present invention relates to compounds of the formula I
wherein A1, A2, R1, R2, R3, X and n are as defined below, which are valuable pharmaceutically active compounds for the therapy and prophylaxis of diseases, for example for cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I are capable of modulating the body""s production of cyclic guanosine monophosphate (xe2x80x9ccGMPxe2x80x9d) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of the formula I, to their use for the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical preparations which comprise compounds of the formula I.
cGMP is an important intracellular messenger which triggers a multitude of different effects via the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels. Examples are the relaxation of smooth muscles, the inhibition of thrombocyte activation and the inhibition of the proliferation of smooth-muscle cells and of leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases as a response to a number of extracellular and intracellular stimuli. In the case of the particulate guanylate cyclases, stimulation is essentially effected by peptidic messengers, such as the atrial natriuretic peptide or the cerebral natriuretic peptide. The soluble guanylate cyclases (xe2x80x9csGCxe2x80x9d), which are cytosolic heterodimeric heme proteins, in contrast, are essentially regulated by a family of low-molecular-weight factors which are formed enzymatically. The most important stimulant is nitrogen monoxide (xe2x80x9cNOxe2x80x9d) or a closely related species. The function of other factors such as carbon monoxide or the hydroxyl radical is still largely unclear. The binding of NO to the heme with formation of a penta-coordinate heme-nitrosyl complex is being discussed as activation mechanism of the activation by NO. The associated release of the histidine which is bound in the basal state to the iron converts the enzyme into the active conformation.
Active soluble guanylate cyclases are composed of an xcex1 and a xcex2 subunit each. Several subunit subtypes have been described which differ from one another with respect to sequence, tissue-specific distribution and expression in different development stages. The subtypes xcex11 and xcex21 are mainly expressed in brain and lung, while xcex22 is found in particular in liver and kidney. The subtype xcex12 was shown to be present in human fetal brain. The subunits referred to as xcex13 and xcex23 were isolated from human brain and are homologous to xcex11 and xcex21. More recent works indicate an xcex12i subunit which contains an insert in the catalytic domain. All subunits show great homologies in the region of the catalytic domain. The enzymes presumably contain one heme per heterodimer, which is bound via xcex21-Cys-78 and/or xcex21-His-105 and is part of the regulatory center.
Under pathologic conditions, the formation of guanylate-cyclase-activating factors can be reduced, or their degradation may be promoted owing to the increased occurrence of free radicals. The resulting reduced activation of the sGC leads, via a weakening of the respective cGMP-mediated cellular response, for example to an increase of the blood pressure, to platelet activation or to increased cell proliferation and cell adhesion. As a consequence, formation of endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thromboses, myocardial infarction, strokes or erectile dysfunction results. Pharmacological stimulation of sGC offers a possibility to normalize cGMP production and therefore makes possible the treatment and/or prevention of such disorders.
For the pharmacological stimulation of the sGC, use has hitherto almost exclusively been made of compounds whose activity is based on an intermediate NO release, for example organic nitrates. The drawback of this treatment is the development of tolerance and a reduction of activity, and the higher dosage which is required because of this.
Various sGC stimulators which do not act via NO release were described by Vesely in a series of publications. However, the compounds, most of which are hormones, plant hormones, vitamins or natural compounds such as, for example, lizard poisons predominantly only have weak effects on the cGMP formation in cell lysates. D. L. Vesely, Eur. J. Clin. Invest., vol.15, 1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm., vol. 88, 1979, p.1244. A stimulation of heme-free guanylate cyclase by protoporphyrin IX was demonstrated by Ignarro et al., Adv. Pharmacol., vol. 26, 1994, p. 35. Pettibone et al., Eur. J. Pharmacol., vol. 116, 1985 p. 307, described an antihypertensive action of diphenyliodonium hexafluorophosphate and attributed this to a stimulation of sGC. According to Yu et al., Brit. J. Pharmacol, vol. 114, 1995, p.1587, isoliquiritigenin, which has a relaxing action on isolated rat aortas, also activates sGC. Ko et al., Blood vol. 84, 1994, p. 4226, Yu et al., Biochem. J. vol. 306, 1995, p. 787, and Wu et al., Brit. J. Pharmacol. vol. 116, 1995, p. 1973, demonstrated a sGC-stimulating activity of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated an antiproliferative and thrombocyte-inhibiting action. Pyrazoles and fused pyrazoles which exhibit a sGC-stimulating activity are described in European Patent Application No. 908,456 and German Patent Application No. 19,744,027.
A series of 2-sulfonylaminobenzoic acid N-arylamides, the N-aryl group of which carries a thio substituent, have been mentioned in the literature. These compounds in which the N-aryl group generally carries as further substituents groups which are readily oxidizable such as, for example, two hydroxy groups being in para position with respect to one another and which in this case can be regarded as hydroquinone derivatives, are auxiliaries for the preparation of photographic materials (see, for example, Chemical Abstracts 119, 105757; 120, 41858; 123, 70224; or 126, 257007). If isolated structural elements are considered then the N-aryl group in these known compounds corresponds to the group R1xe2x80x94S(O)nxe2x80x94A1 in formula I in case A1 denotes a 1,4-phenylene residue which in positions 2 and 5 carries hydroxy groups (or oxy substituents), and the number n is 0. British patent publication No. 876,526 (Chemical Abstracts 56, 15432e) discloses 3,5-dichloro-2-methylsulfonylaminobenzoic acid N-(5-chloro-2-(4-chlorophenylmercapto)-phenyl)-amide which can be used for the protection of wool against moths. Compounds covered by British patent publication No. 876,526 correspond to compounds of the formula I if simultaneously the ring A1 which comprises the carbon atoms which carry the groups C(xe2x95x90X)xe2x80x94NHxe2x80x94 and NHxe2x80x94SO2R2, together with the residues R3, is a benzene ring which carries one to four halogen atoms from the series chlorine and bromine, R2 is (C1-C4)-alkyl, X is oxygen and the group R1xe2x80x94S(O)nxe2x80x94A1xe2x80x94 is a phenylmercaptophenyl-residue (=phenylthiophenyl-) which is substituted by halogen and/or trifluoromethyl and which can also be substituted by methyl or (C1-C4)-alkoxy, and the total number of halogen atoms and trifluoromethyl groups is greater than two. Pharmacological activities of these known 2-sulfonylaminobenzoic acid N-arylamides are not disclosed.
Surprisingly, it has now been found that the compounds of the present invention effect a strong activation of guanylate cyclase and are therefore suitable for the therapy and prophylaxis of disorders which are associated with a low cGMP level.
Thus, the present invention relates to compounds of the formula I:
wherein
A1 is a divalent residue from the series phenylene, naphthylene and heteroarylene which can all be substituted by one or more identical or different substituents from the series halogen, (C1-C5)-alkyl, phenyl, tolyl, CF3, NO2, OH, xe2x80x94Oxe2x80x94(C1-C5)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl, (C1-C2)-alkylenedioxy, NH2, xe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94N((C1-C3)-alkyl)2, xe2x80x94NHxe2x80x94CHO, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N((C1-C3)-alkyl)2, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, heterocyclyl, CHO, xe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94S(O)nxe2x80x94(C1-C4)-alkyl, xe2x80x94S(O)n-phenyl and xe2x80x94S(O)n-tolyl;
the ring A2 which comprises the carbon atoms which carry the groups C(xe2x95x90X)xe2x80x94NHxe2x80x94 and NHxe2x80x94SO2R2 is a benzene ring, a naphthalene ring, a saturated or partially unsaturated 3-membered to 7-membered carbocycle, a saturated or partially unsaturated or aromatic monocyclic 5-membered to 7-membered heterocycle which contains one or more ring heteroatoms from the series N, O and S, or a saturated or partially unsaturated or aromatic bicyclic 8-membered to 10-membered heterocycle which contains one or more ring heteroatoms from the series N, O and S;
R1 is aryl, heterocyclyl or (C1-C18)-alkyl which can be substituted by one or more identical or different residues R4 or, if the number n in the group R1xe2x80x94S(O)nxe2x80x94 is 2, R1 can also be NR5R6 or, if the number n in the group R1xe2x80x94S(O)nxe2x80x94 is O, R1 can also be xe2x80x94CN;
R2 is aryl, heterocyclyl, NR5R6 or (C1-C10)-alkyl which can be substituted by one or more identical or different residues R4;
R3 denotes one or more identical or different residues from the series hydrogen, halogen, CF3, OH, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C7)-alkyl, xe2x80x94O-aryl, (C1-C2)-alkylenedioxy, NO2, xe2x80x94ON, NR7R8, xe2x80x94COxe2x80x94NR7R8, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, heterocyclyl, xe2x80x94S(O)nxe2x80x94(C1-C5)-alkyl and (C1-C5)-alkyl which can be substituted by one or more identical or different residues R4;
R4 is fluorine , OH, xe2x80x94Oxe2x80x94(C1-C10)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C7)-alkyl, xe2x80x94O-aryl, xe2x80x94CN, NR7R8, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N((C1-C3)-alkyl)2, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, heterocyclyl or oxo;
R5 is hydrogen, (C1-C10)-alkyl which can be substituted by one or more identical or different substituents R4 and/or by aryl, or is aryl, heterocyclyl, xe2x80x94COxe2x80x94NR7R8, xe2x80x94CO-aryl or xe2x80x94COxe2x80x94(C1-C10)-alkyl wherein the alkyl residue can be substituted by one or more identical or different residues R4;
R6 independently of R5 has one of the meanings indicated for R5, or
R5 and R6 together with the nitrogen atom to which they are bonded form a 5-membered to 8-membered saturated or partially unsaturated ring which in addition to the nitrogen atom which carries the groups R5 and R6 can contain one or more further ring heteroatoms from the series N, O and S and which can be substituted by one or more identical or different substituents from the series fluorine, (C1-C5)-alkyl, hydroxy-(C1-C3)-alkyl-, xe2x80x94(C1-C3)-alkyl-Oxe2x80x94(C1-C4)-alkyl, aryl, CF3, OH, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94O-aryl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C7)-alkyl, (C2-C3)-alkylenedioxy, NR7R8, CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N(C1-C3)-alkyl)2, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, CHO, xe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94S(O)nxe2x80x94(C1-C4)-alkyl, xe2x80x94S(O)nxe2x80x94NH2, xe2x80x94S(O)nxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94S(O)nxe2x80x94N((C1-C3)-alkyl)2, oxo, xe2x80x94(CH2)mxe2x80x94NH2, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(C1-C4)-alkyl and xe2x80x94(CH2)mxe2x80x94N((C1-C4)-alkyl)2 where in the substituent -(CH2)mxe2x80x94N((C1-C4)-alkyl)2 the two alkyl groups can be connected by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which besides that nitrogen atom and the carbon atoms can additionally contain an oxygen atom, a sulfur atom or a group NR5 as ring member;
R7 is hydrogen or (C1-C7)-alkyl which can be substituted by one or more identical or different substituents from the series OH, xe2x80x94Oxe2x80x94(C1-C5)-alkyl, NH2, xe2x80x94NHxe2x80x94(C1-C4) alkyl and xe2x80x94N((C1-C4)-alkyl)2 where in the substituent N((C1-C4)-alkyl)2 the two alkyl groups can be connected by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which besides that nitrogen atom and the carbon atoms can additionally contain an oxygen atom, a sulfur atom or a group NR5 as ring member;
R8 independently of R7 has one of the meanings of R7 or is xe2x80x94COxe2x80x94(C1-C4)-alkyl;
xe2x80x9carylxe2x80x9d is phenyl, naphthyl or heteroaryl which can all be substituted by one or more identical or different substituent from the series halogen, (C1-C5)-alkyl, phenyl, tolyl, CF3, xe2x80x94Oxe2x80x94CF3, NO2, OH, xe2x80x94Oxe2x80x94(C1-C5)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl, (C1-C2)-alkylenedioxy, NH2, xe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94N((C1-C3)-alkyl)2, xe2x80x94NHxe2x80x94CHO, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N((C1-C3)-alkyl)2, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, heterocyclyl, CHO, xe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94S(O)nxe2x80x94(C1-C4)-alkyl, xe2x80x94S(O)n-phenyl and xe2x80x94S(O)n-tolyl;
xe2x80x9cheteroarylxe2x80x9d and xe2x80x9cheteroarylenexe2x80x9d are a residue of a monocyclic 5-membered or 6-membered aromatic heterocycle or of a bicyclic 8-membered to 10-membered aromatic heterocycle each of which contains one or more ring heteroatoms from the series N, O and S;
xe2x80x9cheterocyclylxe2x80x9d is a residue of a monocyclic or polycyclic 5-membered to 11-membered saturated or partially unsaturated heterocycle which contains one or more ring heteroatoms from the series N, O and S and which can be substituted by one or more identical or different substituents from the series fluorine, (C1-C5)-alkyl, OH, xe2x80x94Oxe2x80x94(C1-C5)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl, NH2, xe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94N((C1-C3)-alkyl)2, xe2x80x94CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N((C1-C3)-alkyl)2, xe2x80x94COxe2x80x94OH and xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl;
n is 0, 1 or 2;
m is 2, 3 or4;
X is O or NH or X is a nitrogen atom which via a single bond is attached to a ring carbon atom in the group A1 which ring carbon atom is directly adjacent to the carbon atom in A1 carrying the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94 so that the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94 together with the carbon atoms in A1 carrying it forms an anellated imidazole ring;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts;
where, however, the compound of formula I is excluded wherein simultaneously the ring A2 which comprises the carbon atoms which carry the groups C(xe2x95x90X)xe2x80x94NHxe2x80x94 and NHxe2x80x94SO2R2 is a benzene ring which is substituted in positions 3 and 5 by chlorine, R2 is methyl, X is oxygen and R1xe2x80x94S(O)nxe2x80x94A1xe2x80x94 is a 5-chloro-2-(4-chlorophenylmercapto)-phenyl residue.
If groups or substituents can occur several times in the compounds of formula I such as, for example R3, R4, R5, aryl, heterocyclyl, alkyl, or the numbers n and m, they can all independently of one another have the meanings indicated and can in each case be identical or different.
Alkyl residues can be straight-chain or branched. This also applies when they are part of other groups, for example in alkoxy groups, alkoxycarbonyl groups or amino groups, or when they are substituted. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, the n-isomers of these residues, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl. The term alkyl here also expressly includes unsaturated alkyl residues, I. e. alkyl residues which contain one or more double bonds and/or one or more triple bonds such as, for example, alkenyl residues and alkinyl residues. Of course, an unsaturated alkyl group contains at least two carbon atoms. Specific alkyl groups whose number of carbon atoms can vary from 1 to a given upper limit, thus also comprise unsaturated alkyl groups whose number of carbon atoms can vary from 2 to the given upper limit. Examples of such residues are the vinyl residue, the 1-propenyl residue, the 2-propenyl residue (allyl residue), the 2-butenyl residue, the 2-methyl-2-propenyl residue, the 3-methyl-2-butenyl residue, the ethinyl residue, the 2-propinyl residue (propargyl residue), the 2-butinyl residue or the 3-butinyl residue. Further, the term alkyl here also expressly includes alkyl residues in which by an internal ring closure within the alkyl group a cyclic system is formed, i. e. the term alkyl also includes saturated and partially unsaturated cycloalkyl residues and cycloalkyl-alkyl- residues (alkyl substituted by cycloalkyl). Of course, a monocyclic cycloalkyl group contains at least three carbon atoms.
Specific alkyl groups whose number of carbon atoms can vary from 1 to a given upper limit, thus also comprise monocyclic cycloalkyl groups whose number of carbon atoms can vary from 3 to the given upper limit, and appropriate cycloalkyl-alkyl- groups. Examples of such cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl which can all also be substituted by one or more identical or different (C1-C4)-alkyl residues, in particular by methyl. Examples of such substituted cycloalkyl residues are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl. Furthermore, unless stated otherwise the term alkyl here also expressly includes unsubstituted alkyl residues as well as alkyl residues which are substituted by one or more, for example one, two, three or four, identical or different aryl residues. The term alkyl thus here also expressly includes arylalkyl- residues such as, for example, aryl-(C1-C4)-alkyl-, for example benzyl residues, phenylethyl residues or indanyl residues. In substituted alkyl residues, for example arylalkyl-, hydroxyalkyl- such as xe2x80x94(C1-C3)-alkyl-OH or alkoxyalkyl- such as xe2x80x94(C1-C3)-alkyl-Oxe2x80x94(C1-C4)-alkyl, the substituents can be present in any desired position.
A saturated or partially unsaturated 3-membered to 7-membered carbocycle representing the ring A2 can be derived from the monocyclic parent systems cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane. If the carbocycle is unsaturated it can contain, for example, one double bond or, in the case of a 5-membered ring, 6-membered ring or 7-membered ring, also two double bonds which can be isolated or conjugated. Double bonds can be present in any positions with respect to the groups C(xe2x95x90X)xe2x80x94NHxe2x80x94 and NHxe2x80x94SO2xe2x80x94R2, i.e., for example a double bond can also be present between the two ring carbon atoms which carry these two groups.
Unless stated otherwise, phenyl residues, naphthyl residues and heterocyclic residues, for example heteroaryl residues, can be unsubstituted or can carry one or more, for example one, two, three or four, identical or different substituents which can be in any desired positions. Unless stated otherwise, in these residues for example those substituents can be present which are indicated as substituents of an aryl group. A preferred series of substituents that can be present in the residue aryl is formed by the substituents halogen, (C1-C5)-alkyl, phenyl, tolyl, CF3, NO2, OH, xe2x80x94Oxe2x80x94(C1-C5)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl, (C1-C2)-alkylenedioxy, NH2, xe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94N((C1-C3)-alkyl)2, xe2x80x94NHxe2x80x94CHO, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N((C1-C3)-alkyl)2, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, heterocyclyl, CHO, xe2x80x94COxe2x80x94(C1-C5)-alkyl, xe2x80x94S(O)nxe2x80x94(C1-C4)-alkyl, xe2x80x94S(O)n-phenyl and xe2x80x94S(O)n-tolyl. If in compounds of the formula I nitro groups are present as substituents, in total only up to two nitro groups can be present in the molecules. If phenyl residues, phenoxy residues, benzyl residues or benzyloxy residues are present as substituents in, for example, aryl residues like phenyl residues and/or in heterocyclic residues then in these substituents the benzene ring can also be unsubstituted or substituted by one or more, for example one, two, three or four, identical or different residues, for example by residues from the series (C1-C4)-alkyl, halogen, hydroxy, (C1-C4)-alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, ((C1-C4)-alkoxy)carbonyl, aminocarbonyl, nitro, amino, (C1-C4)-alkylamino, di-((C1-C4)-alkyl)amino and ((C1-C4)-alkyl)carbonylamino.
In monosubstituted phenyl residues the substituent can be in the 2-position, the 3-position or the 4-position, in disubstituted phenyl residues the substituents can be in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl residues the substituents can be in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. Tolyl (i.e., methylphenyl) can be 2-tolyl, 3-tolyl or 4-tolyl. Naphthyl can 1-naphthyl or 2-naphthyl. In monosubstituted 1-naphthyl residues the substituent can be in the 2-position, the 3-position, the 4-position, the 5-position, the 6-position, the 7-position or the 8-position, in monosubstituted 2-naphthyl residues in the 1-position, the 3-position, the 4-position, the 5-position, the 6-position, the 7-position or the 8-position.
The above explanations as well as the following explanations relating to monovalent residues correspondingly apply to the divalent residues phenylene, naphthylene and heteroarylene. The free bonds via which the divalent residues are attached to the adjacent groups can be present on any ring carbon atoms. In the case of a phenylene residue they can be in 1,2-position (ortho-phenylene), 1,3-position (meta-phenylene) or 1,4-position (para-phenylene). In the case of a naphthylene residue the free bonds can be in 1,2-position (=1,2-naphthylene or 1,2-naphthalinediyl) or in 1,3-position, 1,4-position, 1,5-position, 1,6-position, 1,7-position, 1,8-position, 2,3-position, 2,6-position or 2,7-position. In the case of 5-membered ring aromatics containing one heteroatom such as, for example, thiophene or furan, the two free bonds can be in 2,3-position, 2,4-position, 2,5-position or 3,4-position. A divalent residue derived from pyridine can be a 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-pyridinediyl residue. In the case of unsymmetrical divalent residues the present invention includes all positional isomers, i.e., in the case of a 2,3-pyridinediyl residue, for example, it includes the compound in which the one adjacent group is present in the 2-position and the other adjacent group is present in the 3-position as well as the compound in which the one adjacent group is present in the 3-position and the other adjacent group is present in the 2-position.
Heteroaryl residues, heteroarylene residues, heterocyclyl residues, heterocycles representing the ring A2 and rings which are formed by two groups bonded to a nitrogen atom together with this nitrogen atom are preferably derived from heterocycles which contain one, two, three or four identical or different ring heteroatoms, more preferably from heterocycles which contain one, two or three, in particular one or two, identical or different heteroatoms. Unless stated otherwise, the heterocycles can be monocyclic or polycyclic, for example monocyclic, bicyclic or tricyclic. Preferably they are monocyclic or bicyclic. The rings preferably are 5-membered rings, 6-membered ring or 7-membered ring. Examples of monocyclic and bicyclic heterocyclic systems from which residues occurring in the compounds of the formula I can be derived, are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole (=oxazole), ,1,2-oxazole (=isoxazole), 1,3-thiazole (=thiazole), 1,2-thiazole (=isothiazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine, 1,3-thiazepine, indole, benzothiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, thienothiophenes, 1,8-naphthyridine and other naphthyridines, pteridin, or phenothiazine, each of them in saturated form (perhydro form) or in partially unsaturated form (for example in the dihydro form or the tetrahydro form) or in maximally unsaturated form, insofar as the respective forms are known and stable.
Thus, the heterocycles which are suitable also include, for example, the saturated heterocycles pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine. The degree of saturation of heterocyclic groups is indicated in their individual definitions. Unsaturated heterocycles can contain, for example, one, two or three double bonds within the ring system. 5-membered rings and 6-membered rings can in particular also be aromatic.
The residues derived from these heterocycles can be attached via any suitable carbon atom. Nitrogen heterocycles which can carry a hydrogen atom or a substituent on a ring nitrogen atom, for example pyrrole, imidazole, pyrrolidine, morpholine, piperazine etc., can also be attached via a ring nitrogen atom, in particular if the heterocyclic residue in question is bonded to a carbon atom. For example, a thienyl residue can be present as 2-thienyl residue or 3-thienyl residue, a furyl residue as 2-furyl residue or 3-furyl residue, a pyridyl residue as 2-pyridyl residue, 3-pyridyl residue or 4-pyridyl residue, a piperidinyl residue as 1-piperidinyl residue (i.e., piperidino residue), 2-piperidinyl residue, 3-piperidinyl residue or 4-piperidinyl residue, a (thio)morpholinyl residue as 2-(thio)morpholinyl residue, 3-(thio)morpholinyl residue or 4-(thio)morpholinyl residue (i.e., thiomorpholino residue). A residue derived from 1,3-thiazole or imidazole which is attached via a carbon atom can be attached via the 2-position, the 4-position or the 5-position.
Unless stated otherwise the heterocyclic groups can be unsubstituted or can carry one or more, for example one, two, three, or four, identical or different substituents. Substituents in heterocycles can be present in any desired positions, for example in a 2-thienyl residue or 2-furyl residue in the 3-position and/or in the 4-position and/or in the 5-position, in a 3-thienyl residue or 3-furyl residue in the 2-position and/or in the 4-position and/or in the 5-position, in a 2-pyridyl residue in the 3-position and/or in the 4-position and/or in the 5-position and/or in the 6-position, in a 3-pyridyl residue in the 2-position and/or in the 4-position and/or in the 5-position and/or in the 6-position, in a 4-pyridyl residue in the 2-position and/or in the 3-position and/or in the 5-position and/or in the 6-position. Unless stated otherwise, for example those substituents can be present as substituents in heterocyclic groups which are indicated in the definition of the group aryl, and in the case of saturated and partially unsaturated heterocycles as further substituents also the oxo group and the thioxo group can be present. Substituents on a heterocycle as well as substituents on a carbocycle can also form a ring, i.e., to a ring system further rings can be condensed (or anellated) so that, for example, also cyclopenta-condensed, cyclohexa-condensed or benzo-condensed rings can be present. Suitable substituents on a substitutable ring nitrogen atom of a heterocycle are in particular, for example, unsubstituted (C1-C5)-alkyl residues and aryl-substituted alkyl residues, aryl residues, acyl residues such as xe2x80x94COxe2x80x94(C1-C5)-alkyl, or sulfonyl residues such as xe2x80x94SO2xe2x80x94(C1-C5)-alkyl. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts containing a counterion which is derived from a physiologically acceptable acid. Pyridyl residues, for example, can be present as pyridine-N-oxides.
xe2x80x9cHalogenxe2x80x9d is fluorine, chlorine, bromine or iodine, and preferably fluorine or chlorine.
Without limiting the present invention, in the formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih examples of groups of compounds of the invention are shown in which A2 in the formula I has specific denotations. A1, R1, R2, R3, X and n in the formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih are defined as above for the formula I, and the number k in the formula Ib is 1, 2, 3, 4 or 5, in particular 3 or 4.
On the benzene ring depicted in formula Ia which carries the groups C(xe2x95x90X)xe2x80x94NHxe2x80x94 and xe2x80x94NHSO2R2, four positions are present which can carry a residue R3. The compounds of formula Ia can thus carry four residues R3 which, independently of one another, can all be hydrogen or can have a meaning different from hydrogen, i.e., in the compounds of formula Ia the benzene ring depicted in formula Ia can be unsubstituted or can carry one, two, three or four identical or different substituents from the series halogen, CF3, OH, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C7)-alkyl, xe2x80x94O-aryl, (C1-C2)-alkylenedioxy, NO2, xe2x80x94CN, NR7R8, xe2x80x94COxe2x80x94NR7R8, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C5)-alkyl, heterocyclyl, xe2x80x94S(O)nxe2x80x94(C1-C5)-alkyl and (C1-C5)-alkyl which can be substituted by one or more identical or different residues R4. These explanations accordingly also apply to the compounds of formulae Ib to Ih.
The compounds of the formula I wherein X is a nitrogen atom which via a single bond is attached to a ring carbon atom in the group A1 which ring carbon atom is directly adjacent to the carbon atom in A1 carrying the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94 so that the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94 together with the carbon atoms in A1 carrying it forms an anellated imidazole rin(g, are represented by the formula Ii.
A2, R1, R1, R3 and nin the formula Ii are defined as above for the formula I. The ring A3 which has resulted from the group A1 by the formation of a bond to the nitrogen atom representing X and which ring comprises the two carbon atoms depicted in formula Ii carrying the nitrogen atoms of the anellated imidazole ring, is a benzene ring, a naphthalene ring or a heteroaromatic ring, where to these rings the above explanations relating to A1 correspondingly apply.
The present invention includes all stereoisomeric forms of the compounds of the formula I. Centers of asymmetry that are present in the compounds of formula I can all independently of one another have S configuration or R configuration. The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis/trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at the stage of the compounds of the formula I or at the stage of an intermediate during the synthesis. The present invention also includes all tautomeric forms of the compounds of formula I.
If the compounds of the formula I contain one or more acidic or basic groups the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular the pharmaceutically utilizable salts. Thus, the compounds of the formula I which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula I which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their acid addition salts with inorganic or organic acids, for example as salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of the formula I by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present invention also includes all salts of the compounds of the formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts.
The present invention furthermore includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I such as, for example esters, amides, prodrugs and active metabolites.
A1 preferably is a phenylene residue or a 5-membered or 6-membered heteroarylene residue, more preferably phenylene, where all these residues can be unsubstituted or can be substituted as indicated. If the group A1 is substituted, I. e. if it carries one or more further substituents in addition to the group R1xe2x80x94S(O)n, it is preferably substituted by one or two identical or different of the substituents indicated above. Preferably a phenylene residue representing A1 is unsubstituted, I. e. besides the groups R1xe2x80x94S(O)n and C(xe2x95x90X)xe2x80x94NH it carries four hydrogen atoms. The group R1xe2x80x94S(O)n is preferably attached to a carbon atom in A1 which is not directly adjacent to the carbon atom which carries the group C(xe2x95x90X)xe2x80x94NH. If A1 is phenylene the group R1xe2x80x94S(O)n is particularly preferably located in the meta position or in the para position, more particularly preferably in the para position, with respect to the carbon atom which carries the group C(xe2x95x90X)xe2x80x94NH.
The ring A2 which comprises the two carbon atoms which carry the groups R2xe2x80x94SO2xe2x80x94NH and C(xe2x95x90X)xe2x80x94NHxe2x80x94 preferably is an aromatic ring, more preferably a benzene ring or a thiophene ring, particularly preferably a benzene ring, where all these rings can be unsubstituteci or substituted by one ore more residues R3 which are different from hydrogen.
R1 preferably is (C1-C7)-alkyl, NR5R6 or aryl, more preferably NR5R6, phenyl or 5-membered or 6-membered heteroaryl, particularly preferably NR5R6, where all these residues can be unsubstituted or substituted as indicated and where, as stated above, R1 can be NR5R6 if the number n in the group R1xe2x80x94S(O)nxe2x80x94 is 2.
R2 preferably is aryl, more preferably phenyl or 5-membered or 6-membered heteroaryl, particularly preferably phenyl or a residue of a monocyclic 5-membered or 6-membered aromatic heterocycle which contains one or two identical or different heteroatoms from the series N, O and S such as, for example, phenyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridyl etc., in particular phenyl or 2-thienyl, where all these residues can be unsubstituted or substituted as indicated. Preferably an aryl residue representing R2 is substituted. If an aryl residue representing R2 is substituted it is preferably substituted by one, two or three, in particular by one or two, identical or different substituents. Substituents in an aryl residue representing R2 preferably are substituents from the series halogen, CF3, xe2x80x94Oxe2x80x94CF3, NO2, xe2x80x94CN, (C1-C4)-alkyl and xe2x80x94Oxe2x80x94(C1-C4)-alkyl, more preferably substituents from the series F, Cl, Br, CF3, xe2x80x94Oxe2x80x94CF3, NO2, xe2x80x94CN, CH3 and xe2x80x94OCH3. Especially preferably a substituted aryl residue representing R2 is substituted by Cl, for example by one or two, in particular one, chlorine atoms.
The rings representing A2 can be unsubstituted or substituted as indicated. When they are unsubstituted they only carry residues R3 which are hydrogen. When they are substituted they carry one or more residues R3 which are different from hydrogen. Those substituent positions which do not carry a residue R3 which is different from hydrogen, carry hydrogen atoms. If the ring A2 carries one or more residues R3 which are different from hydrogen it preferably carries one or two such residues R3, in particular one such residue R3. Residues R3 which are different from hydrogen are preferably located in positions of the ring A2 which are not directly adjacent to the groups C(xe2x95x90X)xe2x80x94NH and R2xe2x80x94SO2xe2x80x94NH. If A2 is a saturated or partially unsaturated carbocycle, residues R3 which are different from hydrogen preferably are (C1-C4)-alkyl, in particular methyl. If A2 is an aromatic ring, in particular if A2 is a benzene ring, residues R3 which are different from hydrogen preferably are (C1-C3)-alkyl, halogen, (C1-C3)-alkoxy or CF3, more preferably methyl, chlorine or methoxy. If a A2 is an aromatic ring, in particular a benzene ring, it is very particularly preferred if the ring carries one chlorine atom or two methoxy groups as substituents, I. e., if one residue R3 is present which is chlorine or if two residues R3 are present which are methoxy, and the other positions on the benzene ring carry hydrogen atoms. If A2 is a benzene ring residues R3 which are different from hydrogen are preferably located in positions 4 and/or 5 (with respect to the group C(xe2x95x90X)xe2x80x94NH in the 1-position and the group R2xe2x80x94SO2xe2x80x94NH in the 2-position).
If a group is substituted by one or more residues R4 it is preferably substituted by one, two or three, in particular one or two, identical or different residues R4. R4 preferably is hydroxy, (C1-C4)-alkyloxy, di-((C1-C4)-alkyl)amino or heteroaryl.
R5 and R6 preferably are independently of one another hydrogen, (C1-C9)-alkyl, (C1-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl- or 5-membered or 6-membered aryl or together with the nitrogen atom carrying R5 and R6 form a 5-membered to 7-membered heterocycle which in addition to the nitrogen atom carrying the groups R5 and R6 can contain one further ring heteroatom from the series N, O and S and which can be substituted by one or more, for example one, two, three or four, identical or different residues from the series (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, 5-membered or 6-membered aryl, carbamoyl, hydroxy and oxo. It is particularly preferred if R5 and R6 together with the nitrogen atom carrying these residues form a 5-membered, 6-membered or 7-membered heterocycle which in addition to the nitrogen atom carrying the groups R5 and R6 can contain one further ring heteroatom from the series N, O and S and which can be substituted by one or more, for example one, two, three or four, identical or different residues from the series (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, 5-membered or 6-membered aryl, carbamoyl, hydroxy and oxo, in particular (C1-C3)-alkyl such as, for example, methyl. Preferably a heterocycle which is formed from the groups R5 and R6 together with the nitrogen atom carrying these residues is saturated.
An especially preferable heterocycle which is formed by R5 and R6 together with the nitrogen atom carrying these residues, is derived from morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, 1-oxo-thiomorpholine, from dialkylmorpholines such as dimethylmorpholines, from 2,6-dimethylmorpholine, cis-2,6-dimethylmorpholine, 3,5-dimethylmorpholine, cis-3,5-dimethylmorpholine, 1-(pyrimidin-2-yl)-piperazine, piperidine-4-carboxamide, 1-(2-hydroxyethyl)-piperazine, 1-methylpiperazine, 1-ethylpiperazine, from 1-arylpiperazines, from ethyl piperazine-1-carboxylate, piperidine, 2-methylpiperidine, 2,6-dimethylpiperidine, cis-2,6-dimethylpiperidine, 3,5dimethylpiperidine, cis-3,5-dimethylpiperidine, 4-hydroxypiperidine, from 4-oxopiperidine or a ketal thereof like 1,4-dioxa-8-aza-spiro[4.5]decan, from tetrahydropyridine, tetrahydropyrimidine, 1-methylhomopiperazine, thiazolidine, pyrroline, pyrrolidine, 3-hydroxypyrrolidine, 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydro-1H-isoindole, where these rings are attached via the ring nitrogen atom or, in the case of piperazine derivatives, via the unsubstituted ring nitrogen atom. A more especially preferable heterocycle which is formed by R5 and R6 together with the nitrogen atom carrying these residues, is derived from morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, 1-oxo-thiomorpholine, 2,6-dimethylmorpholine, cis-2,6-dimethylmorpholine, 3,5-dimethylmorpholine, cis-3,5-dimethylmorpholine, 1-(pyrimidin-2-yl)-piperazine, piperidine-4-carboxamide, 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydro-1H-isoindole, moreover preferably from morpholine, 2,6-dimethylmorpholine or cis-2,6-dimethylmorpholine, in particular from morpholine or cis-2,6-dimethylmorpholine, where these rings are attached via the ring nitrogen atom or, in the case of the piperazine derivative, via the unsubstituted ring nitrogen atom.
R7 preferably is hydrogen, (C1-C3)-alkyl, ((C1-C4)-alkyl)2Nxe2x80x94(C1-C3)-alkyl- or (C1C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl-.
R8 preferably is hydrogen, (C1-C3)-alkyl or acetyl.
Aryl preferably is phenyl or heteroaryl, in particular phenyl or 5-membered or 6-membered heteroaryl. Unless stated otherwise, preferred substituents on aryl residues are halogen, CF3, (C1-C3)-alkyl, cyano, nitro and (C1-C3)-alkyloxy, more preferred substituents are CF3, chlorine, methyl and methoxy.
Heteroaryl and heteroarylene preferably are a residue of a monocyclic 5-membered or 6-membered aromatic heterocycle, in particular a residue derived from the heteroaromatics thiophene, pyrazole, thiazole, oxazole, isoxazole, pyridine, pyrimidine, pyridazine and tetrazole.
Heterocyclyl preferably is a residue derived from a saturated heterocycle, more preferably a residue of a monocyclic 5-membered or 6-membered saturated heterocycle, in particular a residue which is derived from pyrrolidine, piperidine, from N-alkylpiperazines, from morpholine, from dialkylmorpholines, from thiomorpholine or tetrahydrofuran. In addition, the above explanations on preferred heterocycles which are formed by the residues R5 and R6 together with the nitrogen atom carrying these residues correspondingly apply to heterocyclyl residues which are attached via a ring nitrogen atom.
If a group S(O)n is bonded to a nitrogen atom the number n therein preferably is 1 or 2, more preferably 2. The number n in the group R1xe2x80x94S(O)n preferably is 0 or 2, particularly preferably 2.
X preferably is O or a nitrogen atom which via a single bond is attached to a ring carbon atom in the group A1 which ring carbon atom is directly adjacent to the carbon atom in A1 carrying the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94 so that the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94 together with the carbon atoms in A1 carrying it forms an anellated imidazole ring. Particularly preferably X is O.
Preferred compounds of the formula I are those compounds in which one or more of the residues contained therein have preferred meanings, all combinations of preferred substituent definitions being a subject of the present invention. Also with respect to all preferred compounds of the formula I the present invention includes all stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. Groups of preferred compounds are also formed, for example, by the compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih in which one or more residues have preferred meanings, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.
A group of particularly preferred compounds is formed, for example, by compounds of the formula I in which
A1 is phenylene or heteroarylene where these residues can be unsubstituted or substituted by one or more identical or different substituents from the series halogen, (C1-C4)-alkyl, CF3, xe2x80x94Oxe2x80x94(C1-C4)-alkyl and xe2x80x94CN;
the ring A2 which comprises the two carbon atoms which carry the groups R2xe2x80x94SO2xe2x80x94NH and C(xe2x95x90X)xe2x80x94NHxe2x80x94 is an aromatic ring;
R1 is (C1-C7)-alkyl which can be substituted by one or more identical or different residues R4, or is aryl, or if the number n in the group R1xe2x80x94S(O)nxe2x80x94 is 2 also is NR5R6;
R2 is aryl;
R3 denotes one or more identical or different residues from the series hydrogen, halogen, CF3, OH, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl, xe2x80x94O-aryl, NO2, xe2x80x94CN, NR7R8, xe2x80x94COxe2x80x94NR7R8, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, heterocyclyl, xe2x80x94S(O)nxe2x80x94(C1-C4)-alkyl and (C1-C4)-alkyl which can be substituted by one or more identical or different residues R4;
R4 is fluorine, OH, xe2x80x94Oxe2x80x94(C1-C10)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkyl-Oxe2x80x94(C1-C7)-alkyl, xe2x80x94O-aryl, xe2x80x94CN, NR7R8, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94(C1-C3)-alkyl, xe2x80x94COxe2x80x94N((C1-C3)-alky)2, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, heterocyclyl or oxo;
R5 and R6 independently of one another are hydrogen, (C1-C9)-alkyl, (C1-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl- or aryl or together with the nitrogen atom carrying R5 and R6 form a 5-membered to 7-membered heterocycle which in addition to the nitrogen atom carrying the groups R5 and R6 can contain one further ring heteroatom from the series N, O and S and which can be substituted by one or more identical or different residues from the series (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, aryl, carbamoyl, hydroxy and oxo;
R7 is hydrogen, (C1-C3)-alkyl, ((C1-C4)-alkyl)2Nxe2x80x94(C1-C3)-alkyl- or (C1-C4)-alkyl-Oxe2x80x94(C1-C3)-alkyl-;
R8 is hydrogen, (C1-C3)-alkyl or acetyl;
xe2x80x9carylxe2x80x9d is phenyl or heteroaryl which can all be substituted by one or more identical or different substituents from the series halogen, (C1-C4)-alkyl, phenyl, CF3, NO2, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, (C1-C2)-alkylenedioxy, NH2, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4)-alkyl, xe2x80x94CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94OH and xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl;
heteroaryl and heteroarylene are a residue of a monocyclic 5-membered or 6-membered aromatic heterocycle which contains one or more identical or different ring heteroatoms from the series N, O and S;
heterocyclyl is a residue of a monocyclic 5-membered or 6-membered saturated heterocycle which contains one or more identical or different ring heteroatoms from the series N, O and S and which can be substituted by one or more identical or different substituents from the series fluorine, (C1-C4)-alkyl, OH, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, NH2, xe2x80x94CN, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94OH and xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl;
n is 0, 1 or 2;
X is oxygen;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.
A group of more particularly preferred compounds is formed, for example, by compounds of the formula I in which:
A1 is phenylene which is unsubstituted or substituted by one or more identical or different substituents from the series halogen, (C1-C4)-alkyl, CF3, xe2x80x94Oxe2x80x94(C1-C4)-alkyl and xe2x80x94CN;
the ring A2 which comprises the two carbon atoms which carry the groups R2xe2x80x94SO2xe2x80x94NH and C(xe2x95x90X)xe2x80x94NHxe2x80x94 is a benzene ring;
R1 is NR5R6;
R2 is aryl;
R3 denotes one or more identical or different residues from the series hydrogen, halogen, CF3, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94CN and (C1-C4)-alkyl;
R5 and R 6 together with the nitrogen atom carrying R5 and R6 form a 5-membered or 6-membered saturated heterocycle which in addition to the nitrogen atom carrying the groups R 5and R6 can contain one further ring heteroatom from the series N, O and S and which can be substituted by one or more identical or different residues from the series (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, aryl, carbamoyl, hydroxy and oxo;
aryl is phenyl or 5-membered or 6-membered heteroaryl containing one or more identical or different ring heteroatoms from the series N, O and S which residues can all be substituted by one or more identical or different substituents from the series halogen, (C1-C4)-alkyl, CF3, NO2, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C4)-alkyl and xe2x80x94CN;
n is 2;
X is oxygen;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.
A group of especially preferred compounds is formed, for example, by compounds of the formula I in which:
A1 is an unsubstituted divalent phenylene residue;
the ring A2 which comprises the two carbon atoms which carry the groups R2xe2x80x94SO2xe2x80x94NH and C(xe2x95x90X)xe2x80x94NHxe2x80x94 is a benzene ring;
R1 is NR 5R6;
R2 is aryl;
R3 denotes one or more identical or different residues from the series hydrogen, halogen, xe2x80x94Oxe2x80x94(C1-C4)-alkyl and (C1-C4)-alkyl;
R5 and R6 together with the nitrogen atom carrying R5 and R6 form a saturated 6-membered heterocycle which in addition to the nitrogen atom carrying the groups R5 and R6 can contain one further ring heteroatom from the series N, O and S and which can be substituted by one or more identical or different residues from the series (C1-C3)-alkyl, aryl, oxo and carbamoyl;
aryl is phenyl or 5-membered or 6-membered heteroaryl containing one or more identical or different ring heteroatoms from the series N, O and S which residues can all be substituted by one or more identical or different substituents from the series halogen, (C1-C4)-alkyl, CF3 and xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
n is 2;
X is oxygen;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.
A group of even more preferred compounds is formed, for example, by compounds of the formula I in which:
A1 is an unsubstituted divalent 1,4-phenylene residue;
the ring A2 which comprises the two carbon atoms which carry the groups R2xe2x80x94SO2xe2x80x94NH and C(xe2x95x90X)xe2x80x94NHxe2x80x94, together with the residues R3, is a benzene ring which carries one or two substituents from the series chlorine and methoxy;
R1 is NR5R6;
R2 is phenyl or thienyl which residues are all substituted by one or two chlorine atoms;
R5 and R6 together with the nitrogen atom carrying R5 and R6 form a saturated 6-membered heterocycle which in addition to the nitrogen atom carrying the groups R5 and R6 can contain one further ring heteroatom from the series O and S and which is unsubstituted or substituted by one or two methyl residues;
n is 2;
X is oxygen;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.
The presents invention also relates to processes for the preparation of the compounds of the formula I which are described in the following and by which the compounds of the invention are obtainable. According to Scheme 1 compounds of the invention can be obtained, for example, by first reacting an aminocarboxylic acid of the formula II with a sulfonyl chloride of the formula R2xe2x80x94SO2xe2x80x94Cl or a sulfonic acid anhydride in the presence of a base in a solvent like water, pyridine or an ether. Suitable bases are inorganic bases like sodium carbonate or organic bases like, for example, pyridine or triethylamine. The sulfonylaminocarboxylic acid of the formula III that is obtained can then be activated, for example by reaction with a chlorinating agent like phosphorus pentachloride, phosphorus oxychloride or thionyl chloride in an inert solvent, to give an acid chloride of the formula IV which is then reacted with an arylamine.
The activation of the carboxylic acid group in the compounds of the formula III can, however, also be carried out in a different manner, for example by one of the numerous methods for the formation of amide bonds in peptide chemistry which are well-known to the skilled person, for example by conversion into a mixed anhydride or an activated ester or by using a carbodiimide like dicyclohexylcarbodimide.
The reaction of the activated sulfonylaminocarboxylic acid with an arylamine is favorably carried out in an inert solvent such as, for example, pyridine, tetrahydrofuran or toluene in the absence or in the presence of an inert auxiliary base like, for example, a tertiary amine or pyridine. If the arylamine that is employed in the reaction with the activated carboxylic acid already contains the desired substituent R1xe2x80x94S(O)n then the reaction directly provides the final compound of the formula I. Compounds of the formula I in which the number n in the group R1xe2x80x94S(O)n is 1 or 2 can also be obtained by reacting an activated carboxylic acid with a mercapto substituted arylamine of the formula R1xe2x80x94Sxe2x80x94A1xe2x80x94NH2 and then oxidizing the mercapto group in the compound of the formula V under standard conditions, for example with a peroxide like hydrogen peroxide or a peracid like 3-chloroperbenzoic acid or monoperoxyphthalic acid in a solvent like, for example, methylene chloride or acetone. The activated carboxylic acids can also first be reacted with arylamines of the formula A1xe2x80x94NH2. The resulting reaction product of the formula VI can then be chlorosulfonated under standard conditions and the chlorosulfonyl group can then be converted under standard conditions into the group R1xe2x80x94SO2, for example by reaction with suitable amines in substance or in a solvent like N-methylpyrrolidone, dimethylformamide, toluene or an ether, optionally in the presence of an auxiliary base. In a similar manner the activated carboxylic acids can be reacted with fluorosulfonylarylamines of the formula Fxe2x80x94SO2xe2x80x94A1xe2x80x94NH2 and the fluorosulfonyl intermediates of the formula VII that are obtained can be converted under standard conditions into the compounds of the formula I according to the invention.
The compounds of the formula I according to the invention can furthermore be obtained by reacting the activated sulfonylaminocarboxylic acids, for example the acid chlorides of the formula IV shown in Scheme 1, with a mercaptoarylamine of the formula H2Nxe2x80x94A1xe2x80x94SH which is unsubstituted on the sulfur atom. In a nucleophilic substitution reaction the product of the formula VIII that is obtained can subsequently be alkylated or arylated on the sulfur atom with an alkyl halogenide or an aryl halogenide or another reactive compound under standard conditions and, if desired, be oxidized on the sulfur to give the sulfoxide or the sulfone as explained above with respect to the compounds of the formula V (see Scheme 2).
Compounds of the formula I can also be obtained, for example, by first activating a suitably substituted nitrocarboxylic acid of the formula IX, for example by converting it into the respective acid chloride of the formula X or by another procedure, and then reacting it with a substituted arylamine of the formula R1xe2x80x94S(O)nxe2x80x94A1xe2x80x94NH2 analogously to the procedures described above (see Scheme 3). Here, too, as arylamines fluorosulfonylarylamines of the formula Fxe2x80x94SO2xe2x80x94A1xe2x80x94NH2 can be employed, and in the N-(fluorosulfonylaryl)-carboxamides of the formula XI that are obtained the fluorosulfonyl group can be converted under standard conditions into a group R1xe2x80x94SO2 according to the invention, for example with an amine of the formula HNR5R6.
Before the nitro group is reduced to an amino group, in the nitro intermediates of the formula XII, use can be made of the activating effect of the nitro group on the ring A2 and a suitable residue R3, for example a halogen atom, can be replaced with a different residue R3 by reaction with a nucleophile, for example an amine. The reduction of the nitro group to give an amino group can, for example, be carried out by catalytic hydrogenation in the presence of a noble metal catalyst or, preferably, in the presence of Raney nickel in a solvent like ethanol, glacial acetic acid or an ethanolic solution of hydrogen chloride, or it can be carried out by reduction with a base metal like zinc, tin or iron in the presence of an acid. The reduction can also be carried out, for example, with tin(II) chloride or by reaction with sodium dithionite, favorably in a mixture of methanol, tetrahydrofuran and water as solvent. The sulfonylation of the amino group in the reduction product of the formula XIII with an activated sulfonic acid derivative can be carried out analogously to the reactions described above, for example with a sulfonic acid chloride in pyridine, and finally gives the compound of the formula I.
The compounds of the formula I in which X is a nitrogen atom which via a single bond is attached to a ring carbon atom in the group A1 which ring carbon atom is directly adjacent to the carbon atom in A1 carrying the group xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94, I. e. the benzimidazole derivatives of the formula Ii, can for example be obtained by reacting an activated sulfonylaminocarboxylic acid derivative obtained as described above according to Scheme 1, for example a carboxylic acid chloride of the formula IV, (or also, in analogy to Scheme 3, a nitrocarboxylic acid derivative) with a 1,2-diaminoarene in the presence of a dehydrating agent such as, for example, thionyl chloride or phosphorus pentachloride (see Scheme 4). The reaction is usually carried out in an inert solvent, for example in a hydrocarbon like toluene or xylene. The 1,2-diaminoarene can already contain the final group R1xe2x80x94S(O)n or a precursor group thereof, for example the group R1xe2x80x94S. Subsequent steps, for example reactions on the sulfur atom, can then be carried out as explained above. Just so, unsubstituted 1,2-diaminoarenes can be employed and the resulting products of the formula XIV can be chlorosulfonated, for example with chlorosulfuric acid, and the sulfonyl chlorides that are obtained can be converted into the final compounds containing the group R1xe2x80x94SO2, for example by reaction with a suitable amine.
All reactions for the synthesis of the compounds of the formula I are per se well-known to the skilled person and can be carried out under standard conditions according to or analogously to procedures described in the literature, for example in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley and Sons, New York. Depending on the circumstances of the individual case, in order to avoid side reactions during the synthesis of a compound of the formula I it can be necessary or advantageous to temporarily block functional groups by introducing protective groups and to deprotect them in a later stage of the synthesis, or introduce functional groups in the form of precursor groups which in a later reaction step are converted into the desired functional groups. Such synthetic strategies and protective groups and precursor groups which are suitable in an individual case are known to the skilled person. If desired the compounds of the formula I can be purified by customary purification procedures, for example by recrystallization or chromatography. The starting compounds for the preparation of the compounds of the formula I are commercially available or can be prepared according to or analogously to literature procedures.
The compounds of the formula I according to the invention effect an increase of the cGMP concentration via the activation of the soluble guanylate cyclase (sGC), and they are therefore useful agents for the therapy and prophylaxis of disorders which are associated with a low or decreased cGMP level or which are caused thereby, or for whose therapy or prophylaxis an increase of the present cGMP level is desired. The activation of the sGC by the compounds of the formula I can be examined, for example, in the activity assay described below.
Disorders and pathological conditions which are associated with a low cGMP level or in which an increase of the cGMP level is desired and for whose therapy and prophylaxis it is possible to use compounds of the formula I are, for example, cardiovascular diseases, such as endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, stable and unstable angina pectoris, thromboses, restenoses, myocardial infarction, strokes, cardiac insufficiency or pulmonary hypertonia, or, for example, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency and diabetes. Compounds of the formula I can additionally be used in the therapy of cirrhosis of the liver and also for improving a restricted memory performance or ability to learn.
The compounds of the formula I and their physiologically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical preparations. A subject of the present invention therefore also are the compounds of the formula I and their physiologically acceptable salts for use as pharmaceuticals, their use for activating soluble guanylate cyclase, for normalizing a disturbed cGMP balance and in particular their use in the therapy and prophylaxis of the abovementioned syndromes as well as their use for preparing medicaments for these purposes.
Furthermore, a subject of the present invention are pharmaceutical preparations (or pharmaceutical compositions) which comprise as active component an effective dose of at least one compound of the formula I and/or a physiologically acceptable salt thereof and a customary pharmaceutically acceptable carrier, I. e. one or more pharmaceutically acceptable carrier substances and/or additives. A subject of the present invention is also those compounds of the formula I which were already known per se and which are excluded by disclaimer from the above-defined compounds of the formula I which are per se a subject of the present invention, and their physiologically acceptable salt as activators of soluble guanylate cyclase.
All statements above and below relating to the pharmacological effects and the uses of the compounds of the formula I thus also apply to the compound of the formula I wherein simultaneously the ring A2 which comprises the carbon atoms which carry the groups C(xe2x95x90X)xe2x80x94NHxe2x80x94 and NHxe2x80x94SO2R2 is a benzene ring which is substituted in positions 3 and 5 by chlorine, R2 is methyl, X is oxygen and R1xe2x80x94S(O)nxe2x80x94A1xe2x80x94 is a 5-chloro-2-(4-chlorophenylmercapto)-phenyl residue, and its physiologically acceptable salts.
Thus, a subject of the invention are, for example, said compound and its physiologically acceptable salts for use as a pharmaceutical, pharmaceutical preparations which comprise as active component an effective dose of said compound and/or a physiologically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and/or a physiologically acceptable salt thereof in the therapy or prophylaxis of the abovementioned syndromes as well as their use for preparing medicaments for these purposes.
The pharmaceuticals according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.
The amount of active compound of the formula I and/or its physiologically acceptable salts in the pharmaceutical preparations normally is from 0.2 to 500 mg, preferably from 1 to 200 mg, per dose, but depending on the type of the pharmaceutical preparation it can also be higher. The pharmaceutical preparations usually comprise 0.5 to 90 percent by weight of the compounds of the formula I and/or their physiologically acceptable salts. The preparation of the pharmaceutical preparations can be carried out in a manner known per se. For this purpose, one or more compounds of the formula I and/or their physiologically acceptable salts, together with one or more solid or liquid pharmaceutical carrier substances and/or additives (or auxiliary substances) and, if desired, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.
For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules it is possible to use, for example, lactose, starch, for example maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example of solutions for injection, or of emulsions or syrups are, for example, water, physiologically sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of the formula I and their physiologically acceptable salts and to use the resulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
Besides the active compounds and carriers, the pharmaceutical preparations can also contain customary additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
The dosage of the active compound of the formula I to be administered and/or of a physiologically acceptable salt thereof depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to compounds of the formula I. In general, a daily dose of approximately 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, in particular 0.3 to 5 mg/kg (in each case mg per kg of bodyweight) is appropriate for administration to an adult weighing approximately 75 kg in order to obtain the desired results. The daily dose can be administered in a single dose or, in particular when larger amounts are administered, be divided into several, for example two, three or four individual doses. In some cases, depending on the individual response, it may be necessary to deviate upwards or downwards from the given daily dose.
The compounds of the formula I activate the soluble guanylate cyclase, mainly by binding in the heme binding pocket of the enzyme. On account of this property, apart from use as pharmaceutically active compounds in human medicine and veterinary medicine, they can also be employed as a scientific tool or as aids for biochemical investigations in which such an effect on guanylate cyclase is intended, and also for diagnostic purposes, for example in the in vitro diagnosis of cell samples or tissue samples. The compounds of the formula I and salts thereof can furthermore be employed, as already mentioned above, as intermediates for the preparation of other pharmaceutically active compounds.
The following examples of compounds of the formula I and of intermediates for their preparation illustrate the invention without limiting it.


A large number of electric connections, particularly electrical plug connections, are known which serve to transmit electric currents, voltages and/or signals with a largest possible bandwidth. Particularly in the automotive industry, such connections must safeguard a faultless transmission of electric power, signals and/or data in thermally charged, polluted, moist or chemically aggressive surroundings.
Due to a wide range of applications for such connections, a large number of specifically configured electric plug contacts are known, particularly crimp-contacts. In the field of electrical power contacting for the automotive industry, aside from a crimp-contact, only circular high-voltage or high-current contacts are known which could easily be stamped out of milled metal strips. In a rectangular high-voltage or high-current contact, an electric contact is provided by many filigree contact lamellas, wherein all contact lamellas have the same design and are bound to a contact cage at both longitudinal end portions. Due to the position of the contact lamellas in the contact, an amperage varies per contact lamella; a balanced current distribution is not possible with such a contact. Furthermore, the many filigree contact lamellas lead to a non-robust, damageable contact.
A known contact comprises identical contact lamellas wherein some contact lamellas are located more closely to a conductor-crimping section of the contact than several other contact lamellas. When using the contact, because the current always takes the path of least resistance, this leads to the problem that the contact lamellas which are located more closely to the conductor-crimping section carry more electric current than those which are located further away from the conductor-crimping section. The contact lamella located closest to the conductor-crimping section carries the most current and the one furthest away from the conductor-crimping section only carries a very small amount or hardly any current.


The inventors have discovered, during the course of their histological studies on antitumor agents, the novel antitumor antibiotic BMG 162-aF2, later named spergualin, in a broth for culture of Bacillus laterosporus BMG 162-aF2 (Deposit No. 5230 at the Fermentation Research Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry of Japan), a strain belonging to the genus Bacillus (Journal of Antibiotics, Vol. 34, 1619-1622, 1981), The chemical structure of spergualin is represented by the following formula ##STR3## in which the configuration at the 15-position is S-configuration (sinister), but that at the 11-position has not been determined (Journal of Antibiotics, vol. 34, 1622, 1981).
The compound of this structural formula could also be synthesized by the condensation of an acid amide and glyoxylylspermidine, and the resulting epimer was divided into (-)-spergualin that naturally occurs and (+)-spergualin that does not (Journal of Antibiotics, Vol. 34, 1625, 1981).


Embodiments of the present disclosure relate to three-dimensional (3D) memory devices and fabrication methods thereof.
Planar memory cells are scaled to smaller sizes by improving process technology, circuit design, programming algorithm, and fabrication process. However, as feature sizes of the memory cells approach a lower limit, planar process and fabrication techniques become challenging and costly. As a result, memory density for planar memory cells approaches an upper limit.
A 3D memory architecture can address the density limitation in planar memory cells. The 3D memory architecture includes a memory array and peripheral devices for controlling signals to and from the memory array.


(5.1) Field of the Invention
The present invention relates generally to computer programs and, more specifically to a method and apparatus for processing escrow transactions and a method of doing business in escrow transactions using computers and computer network technology. More particularly, the present invention relates to a computerized method and apparatus for escrow transactions and a method of doing business in escrow transaction management, preferably using the Internet.
(5.2) Description of Related Art
(5.2.1) Glossary
The following terms and definitions are provided for the convenience of the reader; no limitation on the scope of the invention is intended by this GLOSSARY nor should any be implied therefrom.
“Client-Server”: A model of interaction in a distributed computer network system in which a program at one site sends a request to another site and then waits for a response. The requesting program is called the “client,” and the program which responds to the request is called the “server.” In the context of the World Wide Web (“www” or “web” defined hereinafter), the client is a “browser;” i.e., a program which runs on a computer of an end-user. A program and network computer which responds to a browser request by serving web pages and the like, is referred to as a “server.” Specialized servers, such as dedicated electronic mail (defined hereinafter) servers are also known in the art.
“Electronic Mail” (“e-mail”): The process and software for sending and receiving of textual information and attachments thereto between end-users over a distributed computer network such as the internet; internet access providers often include e-mail service to its customers as part of the access software that allows the end user to dial into the internet.
“Hypertext Mark-up Language” (“HTML”): A standard coding convention and set of codes for attaching presentation and linking attributes to informational content within documents; the primary standard used for generating web documents. During a document authoring stage, the HTML codes (referred to as “tags”) are embedded within the informational content of the document; when the document is subsequently transferred from a server to a client, the codes are interpreted by the browser and used to parse and display the document. In specifying how the browser is to display the document, HTML tags can be used to create hyperlinks to other web documents.
“HyperText Transport Protocol” (“HTTP”): The standard Internet (infra) client-server protocol used for the exchange of information such as HTML documents and client requests for such documents between a browser and the server. HTTP—or HML or the like—includes a number of different types of messages which can be sent from the client to the server to request different types of server actions. For example, a “get” message which has the format GET<URL> (defined hereinafter) causes the server to return the document or file located at the specified URL.
“Internet”: A generic term for a collection of distributed, interconnected networks (ARPANET, DARPANET, World Wide Web, or the like) that are linked together by a set of industry standard protocols and the like to form a global, distributed network.
Web “Site”: A computer system that serves informational content over a network using standard protocols of the web. Typically, a web site corresponds to a particular internet domain name, such as WIDGET.COM”, and includes the content associated with a particular organization such as Widget Company. The term is generally intended to encompass both (1) the hardware/software server components that serve the informational content over the network, and (2) the “back-end” hardware-software components, including any non-standard or specialized components that interact with the server component to perform service for web site users.
“World Wide Web” (WWW or simply “web”): Refers generally to both (1) a distributed collection of interlinked, user-viewable hypertext documents (“web documents” or “web pages”) that are accessible via the internet, and (2) the client and server software components which provide user access to such documents using standardized internet protocols. Currently, the primary standard protocol for allowing applications to locate and acquire web documents is HTTP, and the web pages are encoded using HTML. However, the terms “web” and WWW or “world wide web” as used herein are intended to encompass future mark-up languages and transport protocols which may be used.
(5.2.2.) Background of the Invention
In the main, an escrow is a third party to a transaction between a seller and a buyer (the buyer and seller are collectively referred to as the “principals”). A deed, a bond, money, a piece of property, or other valuable, is delivered to the third party—hereinafter referred to as the “escrow officer”—to be delivered by the officer to the grantee only upon the fulfillment of all the conditions precedent which are imposed upon the principals and are usually of the express terms and conditions of a purchase and sale agreement (also referred to more simply as the “sales contract” hereinafter). In essence, the property is placed in trust in an escrow account.
Escrow transactions can be for both personal and real property. Some states (e.g. California) provide for the use of licensed escrow agents when a sale of real estate is being transacted. For the purpose of describing the present invention, an exemplary escrow transaction for real estate is considered; no limitation on the scope of the invention is intended by the inventor nor should any be implied therefrom.
While computers are important tools for the buyers and sellers of a valuable property (jointly referred to as the “principals”), in the main, the use of actual purchase agreements, escrow services and associated contracts, such as loan agreements, are handled manually since the true identity of the principals and their agreement by signatur on the assorted contracts and documents involved is a critical, personal factor. Notarization on the more important documents is often required. The coordination of the various entities involved with the transfer of a real estate property—namely the principals, agents, real estate brokers, attorneys, lending institutions such as banks or other mortgage related institutions, insurance companies, government and quasi-governmental entities (such as county clerk offices, local real estate boards, state deed recording and tax departments, and the like), vendors (e.g., title companies, property inspectors, property assessors, home owners associations, and the like), and any and all other entities involved in the transaction to be escrowed, is assigned to a licensed escrow agent. In turn, the escrow agent usually must involve the aid of administrative assistants to track all of the required paperwork and transfer of funds necessary to complete the transaction. As can be imagined, the number of such real estate transactions in a single California county on a daily basis is enormous. Moreover, commercial realty transactions involve even more complex service involving even more service providers.
With the advent of the so-called computer age, lending institution have devised methods and apparatus for processing mortgages and other loans. Mortgages and other transactions involving banks and credit-loan associations have been the subject of computerization for many years. See, e.g., U.S. Pat. Nos.
U.S. Pat. No. 4,876,648, SYSTEM AND METHOD FOR IMPLEMENTING AND ADMINISTERING A MORTGAGE PLAN;
U.S. Pat. No. 5,924,084, NEGOTIATED MATCHING SYSTEM;
U.S. Pat. No. 5,930,776, LENDER DIRECT CREDIT EVALUATION AND LOAN PROCESSING SYSTEM;
U.S. Pat. No. 5,940,811, CLOSED LOOP FINANCIAL TRANSACTION METHOD AND APPARATUS;
U.S. Pat. No. 5,983,206, COMPUTER SYSTEM AND COMPUTER-IMPLEMENTED PROCESS FOR IMPLEMENTING A MORTGAGE PARTNERSHIP;
U.S. Pat. No. 5,966,699, SYSTEM AND METHOD FOR CONDUCTING LOAN AUCTION OVER COMPUTER NETWORK;
U.S. Pat. No. 5,991,745, REVERSE MORTGAGE LOAN CALCULATION SYSTEM AND PROCESS;
U.S. Pat. No. 5,995,947, INTERACTIVE MORTGAGE AND LOAN INFORMATION AND REAL-TIME TRADING SYSTEM;
U.S. Pat. No. 6,012,047, REVERSE MORTGAGE PROCESSING SYSTEM;
U.S. Pat. No. 6,016,482, ENHANCED COLLATERALIZED FUNDING PROCESSOR; and
U.S. Pat. No. 6,029,149, LENDER DIRECT CREDIT EVALUATION AND LOAN PROCESSING SYSTEM.
Buyers are often “pre-qualified” by a lending institution for a particular loan amount even before seeking the right property. As a result, one of the problems of the marketplace is that the cause of delays experienced in valuable property exchange escrow transactions have shifted from the lending institution to the escrow agent. In some states, e.g., California, real estate transactions are regularly conducted via an escrow.
With the establishment of the internet, the world wide web, and the like, the emergence of e-commerce has generated a need for a computerized method and apparatus for processing escrow transactions and a method of managing escrows using such tools.


1. Field of the Invention
The present invention relates to an oscillating angular speed sensor.
2. Description of Related Art
JP-A-2002-500961 discloses a micro mechanical component produced by connecting a substrate wafer and a cap wafer. The substrate wafer has a surface structure to detect a physical quantity. The cap wafer has a recess opposing to the surface structure of the substrate wafer, such that the surface structure can be prevented from having a contact from outside. The cap wafer is bonded to the substrate wafer, and the surface structure is sealed in a space between the wafers.
The space between the wafers is a single closed space, such that the surface structure is arranged in the single space. When the surface structure operates as an oscillating angular speed sensor, the sensor includes a detector to detect an angular speed, and a driving portion to drive the detector in a single direction. In this case, the detector and the driving portion are arranged in the same single space.
However, in a case that gas is filled in the space, when the driving portion drives the detector, oscillation amplitude of the detector may be affected by a damping of the gas. Therefore, it is difficult for the driving portion to drive the detector in the single direction, such that a detection accuracy of the sensor may become worse. Thus, the space may be required to be vacuumed for the driving portion, so as to secure the oscillation amplitude of the detector. However, when the space is vacuumed, the gas cannot have an effect of the damping. Therefore, electrodes of the detector may have damage due to collision or sticking, when an impact is applied to the sensor.
That is, a space suitable for the detector, and a space suitable for the driving portion are different from each other.


Currently, Chinese herbal injections for treatment of cardio-cerebral vascular diseases and fundus diseases include Ixeris Sonchifolia Hance injection, which for clinical application is a brown-yellow transparent liquid derived from Ixeris Sonchifolia Hance of Compositae and extracted as intravenous injection starting from full plants. The main pharmaceutical components of the intravenous injection are flavone and adenosine. The coexistence of phyto-flavone and -adenosine in Ixeris Sonchifolia Hance has shown a remarkable complementary effect for treatment of cardio-cerebral diseases, which has already been demonstrated by pharmacodynamics study and clinical application. The pharmacological effects of Ixeris Sonchifolia Hance injection consist in its efficacies of: 1. increasing coronary artery flow, lowering cardiovascular resistance, resisting myocardial infarction, enhancing collateral circulations, reducing myocardial oxygen consumption and improving cardio-microcirculations, which are useful for the treatment of coronary heart diseases, angina pectoris, chest distress and breath shortness, and myocardial infarction; 2. reducing platelet conglomeration, increasing the activity of fibrinolysin, inhibiting thrombosis, decreasing the viscosity of blood plasma and serum, increasing the electrophoresis velocity of erythrocytes, lowering cerebro-vascular resistance, increasing cerebral blood capacity and promoting restoration of neural function, which are useful in the treatment of cerebral infarction (cerebral thrombosis); 3. improving microcirculation disorders caused by bacteria, systemic microcirculation disorders caused by polymer dextran, and fundus microcirculation, and dilating fundus artery, which are useful in the treatment of fundus diseases, such as central retinitis, optic atrophy and retinitis pigmentosa. However, Ixeris Sonchifolia Hance injections exhibit poor stability and can only stand short-term storage. The contents of flavone and adenosine have been determined by High Performance Liquid chromatography (HPLC) and derivatization method, which show that adenosine content reduces from 15.0 μg/ml prior to finishing of the aqueous injection to 6.7 μg/ml thereafter, while for flavone, from 0.25 mg/ml to 0.169 mg/ml, with a lose of 55.3% and 32.4% of the prescribed, respectively. Six months later, adenosine content reduces to 6.5 μg/ml, while flavone content is 0.133 mg/ml. This can also be verified by subjecting Ixeris Sonchifolia Hance aqueous injection wherein flavone and adenosine contents are respectively 5.07 mg/ml and 24.37 μg/ml, to ten-day accelerated stress test carried out at 80° C. in an oven, followed by content determination of both, in doing so, merely 3.16 mg/ml and 12.18 μg/ml are left for flavone and adenosine, respectively (Tab. 1). In view of the considerable lose of both active ingredients of flavone and adenosine during preparation and storage, the therapeutic effect of the injection is seriously impacted. Moreover, Ixeris Sonchifolia Hance injection exhibits a distinct change in color of solution. The absorbance measured at 400 nm using ultraviolet spectrophotometer during preparation of the aqueous injection from stock extract, ranges from 0.338 prior to sterilization to 0.423 thereafter, and further increases to 0.443 after 6 months with darkened color. It should be further noted that HPLC spectra of the injection exhibit poor similarity, that is to say, there exist major differences among HPLC spectra of different batches of aqueous injections yet formulated from the same stock extract. The stability behavior of same kind of commercial aqueous injections by random sampling (Batch No. 20000303, 20000503, 20010120) shows that: flavone contents are 0.27 mg/ml, 0.51 mg/ml and 0.30 mg/ml, while for adenosine, the contents are 1.11 μg/ml, 0.147 μg/ml and 0.00 μg/ml, respectively
In a conclusion, Ixeris Sonchifolia Hance aqueous injection is susceptible to various factors such as preparation, storage, and thus is difficult to be controlled in quality, which greatly expenses the therapeutic effect of Ixeris Sonchifolia Hance injection.


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