The present invention relates to acylguanidine derivatives of formula (I) in which R1, R2, R4, R5, R6, A, m and n have the meanings indicated in the patent claims, their physiologically tolerable salts and their prodrugs. The compounds of formula (I) are valuable pharmaceutical active ingredients. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts and are suitable, for example, for the therapy or prophylaxis of diseases which are caused at least partially by an undesired extend of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of compounds of formula (I), their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.

The present invention relates to acylguanidine derivatives of the formula I,
in which R1, R2, R4, R5, R6, A, m and n have the meanings indicated below, their physiologically tolerable salts and their prodrugs. The compounds of the formula I are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts and are suitable, for example, for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.
Human bones are subject to a constant dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cell specialized for these purposes. Bone resorption is based on the destruction of bone matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption.
Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus bone resorption during the ongoing remodelling process.
Conventional osteoporosis treatment includes, for example, the administration of bisphosphonates, estrogens, estrogen/progesterone (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996, 31, 211).
Activated osteoclasts are polynuclear cells having a diameter of up to 400 xcexcm, which remove bone matrix Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called xe2x80x9csealing zonexe2x80x9d, the region between their cell membrane and the bone matrix. The acidic environment and the proteases cause the destruction of the bone. The compounds of the formula I inhibit bone resorption by osteoclasts.
Studies have shown that the attachment of osteoclasts to the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor xcex1IIbxcex23 on the blood platelets and the vitronectin receptor xcex1vxcex23. The vitronectin receptor xcex1vxcex23 is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor xcex1IIbxcex23, which is expressed on the osteoclast membrane, controls the process of attachment to the bones and bone resorption and thus contributes to osteoporosis. xcex1vxcex23 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) Which inhibit tooth destruction by osteoclasts and the migration of osteociasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. describe echistatin, an RGD peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast adhesion to the bones. Fischer et al. (Endocrinology 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo.
It was furthermore shown that the vitronectin receptor xcex1vxcex23 on human cells of the vascular smooth musculature of the aorta stimulates the migration of these cells into the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815). Yue et al. (Pharmacology Reviews and Communications 1998, 10, 9-18) showed the inhibition of neointima formation using an xcex1vxcex23 antagonist.
Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against xcex1vxcex23 or xcex1vxcex23 antagonists can cause a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. The vitronectin receptor xcex1vxcex23 is also involved in the progression of a variety of other types of cancer, and is overexpressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 1996, 31, 191). The melanoma invasiveness correlated with this overexpression (Stracke et al., Encylopedia of Cancer, volume III, 1855, Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639). Carron et al. (Cancer Res. 1998, 58, 1930) describe the inhibition of tumor growth and the inhibition of hypercalcemia of malignancy using an xcex1vxcex23 antagonist.
Cheresh et al. (Science 1995, 270, 1500) describe anti-xcex1Vxcex23 antibodies or xcex1vxcex23 antagonists which inhibit the bFGF-induced angiogenesis processes in the rat eye, a property which can be used therapeutically in the treatment of retinopathies.
Influencing of the vitronectin receptor or of the interactions in which it is involved thus offers the possibility of influencing different disease states for whose therapy and prophylaxis there continues to be a need for suitable pharmaceutical active ingredients.
The patent application WO-A-94/12181 describes substituted aromatic ring systems and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528 586 and EP-A-528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives. WO-A-95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes benzodiazepines, and WO-A-96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists. WO-A-97/21726 describes agents for promoting bone formation which belong to various classes of compounds, among them tyrosine derivatives containing an unsubstituted guanidino group. Further investigations have shown that the acylguanidines of the formula I are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
The present invention relates to compounds of the formula I,
in which
R1 and R2 independently of one another are hydrogen or (C1-C6)-alkyl which is unsubstituted or substituted by R3, with the proviso that R1 and R2 are not both hydrogen at the same time,
or in which the radicals R1- and R2-together are a saturated or unsaturated bivalent (C2-C9)-alkylene radical, for example the group xe2x80x94(CH2)pxe2x80x94, in which p is 2, 3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more groups from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C9)-alkylene radical;
R3 is (C1-C8)-alkyl, (C1-C8)-alkoxy, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C4)-alkyl- halogen, trifluoromethyl, hydroxyl, nitro or amino;
R4 is hydrogen, (C1-C6)-alkyl-COxe2x80x94Oxe2x80x94(C1-C4)-alkyl- or (C1-C6)-alkyl, which is unsubstituted or is substituted by a radical from the group consisting of hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94, NR7R7xe2x80x2and N+R7R7xe2x80x2R7xe2x80x3Qxe2x88x92, where R7, R7xe2x80x2 and R7xe2x80x2 independently of one another are hydrogen, (C1-C6)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C6)-alkyl- and Qxe2x88x92 is a physiologically tolerable anion, or in which R4 is one of the radicals
xe2x80x83in which the bonds, via which the radicals are bonded, are indicated by dashed lines;
R5 is (C1-C8)-alkyl, (C6-C14)-aryl-(C1-6)-alkyl- or (C5-C14)-heteroaryl-(C1-C5)-alkyl-, where the aryl radical or the heteroaryl radical is unsubstituted or is substituted by one, two or three radicals R3,
R6 is hydrogen, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, hydroxyl, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94Oxe2x80x94 or nitro;
A is CH2, O, S or NH;
m is 1, 2or 3;
n is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
All radicals which can occur more than once in the compounds of the formula I, for example the radicals R3, can in each case independently of one another have the meanings indicated, and they can in each case be identical or different. Similarly, all radicals of which it is said that they independently of one another can have a meaning indicated, can in each case be identical or different.
The alkyl radicals occurring in the substituents can be straight-chain or branched and can be saturated or mono-unsaturated or poly-unsaturated. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or arylalkyl radicals. The same applies to alkylene radicals (=alkanediyl radicals). Examples of suitable (C1-C9)-alkyl radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The bivalent radicals corresponding to the abovementioned monovalent radicals, for example methylene, ethylene, 1,3-propylene, 1,2-propylene (=1-methylethylene), 2,3-butylene (=1,2-dimethylethylene), 1,4-butylene, 1,6-hexylene, are examples of alkylene radicals.
Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl radicals such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene radicals, that is alkenylene radicals (=alkenediyl radicals) and alkynylene radicals (=alkynediyl radicals), can likewise be straight-chain or branched. Examples of alkenylene radicals are
vinylene or propenylene, examples of alkynylene radicals are ethynylene or propynylene.
Cycloalkyl radicals can be, for example, monocyclic, bicyclic or tricyclic. Monocyclic cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl, which, however, can also be substituted by, for example, (C1-C4)-alkyl. Examples of substituted cycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
Halogen is, for example, fluorine, chlorine, bromine or iodine.
(C5-C14)-Aryl includes heterocyclic (C5-C14)-aryl radicals (=(C5-C14)-heteroaryl radicals) in which one or more of the 5 to 14 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and carbocyclic (C6-C14)-aryl radicals. Examples of carbocyclic (C5-C14)-aryl radicals are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and in particular phenyl are preferred. If not stated otherwise, aryl radicals, in particular phenyl radicals, can be unsubstituted or substituted by one or more radicals, preferably one, two or three radicals. In particular aryl radicals can be substituted by identical or different radicals from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. Generally, only up to two nitro groups can occur as substituents in the compounds of the formula I according to the invention.
In monosubstituted phenyl radicals, the substituent can be located in the 2-position, the 3-position or the 4-position, the 3- and the 4-position being preferred. If phenyl is disubstituted, the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Preferably, in disubstituted phenyl radicals, the two substituents are arranged in the 3,4-position, relative to the linkage site. In trisubstituted phenyl radicals, the substituents can be in the 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.
Beside carbocyclic systems, (C5-(C14)-aryl groups can also be monocyclic or polycyclic aromatic ring systems in which 1, 2, 3, 4 or 5 of the 5 to 14 ring carbon atoms are replaced by heteroatoms, in particular by identical or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocyclic (C5-C14)-aryl groups and (C5-C14)-heteroaryl groups are 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, xcex2-carbolinyl, or benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivatives of these radicals. The heterocyclic systems can be substituted by the same substituents as the abovementioned carbocyclic aryl systems.
In the series of these heteroaryl groups, monocyclic or bicyclic aromatic ring systems having 1, 2 or 3 heteroatoms, in particular having 1 or 2 heteroatoms, from the group consisting of N, O, S, which can be unsubstituted or substituted by 1, 2 or 3 substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl, are preferred. Particularly preferred here are monocyclic or bicyclic aromatic 5-membered to 1 0-membered ring systems having 1 to 3 heteroatoms, in particular having 1 or 2 heteroatoms, from the group consisting of N, O, S, which can be substituted by 1 to 2 substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyl and benzyloxy.
If the two radicals R1- and R2- together represent a bivalent saturated or unsaturated (C2-C9)-alkylene radical, these two radicals, together with the two nitrogen atoms to which they are bonded, and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a monocyclic 1,3-diazaheterocycle which is bonded to the nitrogen atom in the group (CH2)mxe2x80x94COxe2x80x94NH via its 2-position. Examples of radicals of such 1,3-diazaheterocycles which can be substituted as indicated in the (C2-C9)-alkylene radical and also on the guanidino nitrogen atom, are the 1H-imidazol-2-yl radical, the 4,5-dihydro-1H-imidazol-2-yl radical, the 1,4,5,6-tetrahydro-pyrimidin-2-yl radical or the 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl radical. If a 5-membered to 7-membered ring is fused to a carbon-carbon bond in the (C2-C9)-alkylene radical, then the two radicals R1 and R2, together with the two nitrogen atoms to which they are bonded, and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a bicyclic heterocycle which is bonded to the nitrogen atom in the group (CH2)mxe2x80x94COxe2x80x94NH and which can be substituted as indicated. The fused (or condensed) 5-membered to 7-membered ring can be saturated, mono-unsaturated or di-unsaturated or aromatic. Thus, for example, a cyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane ring or benzene ring can be condensed. Examples of radicals of such bicyclic heterocycles which can be bonded to the nitrogen atom in the group (CH2)mxe2x80x94COxe2x80x94NH are the 1,3a,4,5,6,6a-hexahydro-1,3-diazapentalen-2-yl radical, the 1H-benzimidazol-2-yl radical, the 3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl radical, the 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl radical, the 4,7-dihydro-1H-benzimidazol-2-yl radical or the 1H-imidazo[4,5-b]pyridin-2-yl radical. If a condensed ring is substituted and/or if the (C2-C5)-akylene radical is substituted, they are preferably independently of one another monosubstituted or disubstituted by identical or different radicals R3. If alkyl groups representing R1 and/or R2 are substituted, they are preferably independently of one another monosubstituted or disubstituted, in particular monosubstituted, by identical or different radicals R3.
Optically active carbon atoms contained in the compounds of the formula I can independently of one another have the R configuration or the S configuration. The configurations on different centers can be identical or different. The compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomer mixtures, for example in the form of racemates, or of diastereomer mixtures. The present invention relates to both pure enantiomers and enantiomer mixtures, for example racemates, and diastereomers and diastereomer mixtures. The invention comprises mixtures of two or of more than two stereoisomers of the formula I and all ratios of the stereoisomers in the mixtures. The compounds of the formula I can optionally be present as E isomers or Z isomers. The invention relates to both pure E isomers and pure Z isomers and E/Z mixtures in all ratios. The invention also comprises all tautomeric forms of the compounds of the formula I. For example, beside the form shown in the formula I, also the form in which the acylguanidine units is present as a xe2x80x94COxe2x80x94Nxe2x95x90C(NHR1)xe2x80x94NR2R6 group, and all other forms which differ by different positions of mobile hydrogen atoms are comprised. Diastereomers, including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example, by chromatography on chiral phases or by resolution. Stereochemically uniform compounds can also be obtained by employing stereochemically uniform starting compounds or by using stereoselective reactions.
Physiologically tolerable salts of the compounds of formula I are nontoxic, physiologically acceptable, in particular pharmaceutically utilizable, salts. Such salts of compounds of the formula I which contain acidic groups, for example carboxylic acid groups, are, for example, alkali metal salts or alkaline earth metal salts, such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine or tris-2-hydroxyethyl)amine. Compounds of the formula I which contain basic groups, form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds of the formula I which contain a basic group and an acidic group, for example the guanidino group and a carboxyl group, can be present as zwitterions (betaines), which are likewise included by the present invention.
The physiologically tolerable anion Qxe2x88x92, which is contained in the compounds of the formula I when R4 is an alkyl radical which is substituted by a positively charged ammonium group, is, in particular, a monovalent anion or an eqivalent of a polyvalent anion of a nontoxic, physiologically acceptable, in particular also pharmaceutically utilizable, inorganic or organic acid, for example the anion or an anion equivalent of one of the abovementioned acids suitable for the formation of acid addition salts. Qxe2x88x92 can thus be, for example, one of the anions (or an anion equivalent) chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate or p-toluenesulfonate.
Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals, but are suitable, for example, as intermediates for carrying out other chemical modifications of the compounds of the formula I or as starting materials for the preparation of physiologically tolerable salts.
The present invention moreover 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, for example esters and other prodrugs and other physiologically tolerable derivatives, as well as active metabolites of the compounds of the formula I. The invention relates in particular to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs for the compounds of the formula I, i.e. chemically modified derivatives of the compounds of the formula I having properties which are improved in a desired manner, are known to those skilled in the art. More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350. Suitable prodrugs for the compounds of the formula I are especially ester prodrugs, for example (C1-C4)-alkyl esters, of carboxylic acid groups, in particular of the COOH group, which is present when R4 in the group COOR4 is hydrogen, and also acyl prodrugs and carbamate prodrugs of acylatable a nitrogen-containing groups such as amino groups and in particular the guanidino group. In the acyl prodrugs or carbamate prodrugs, one or more times, for example twice, a hydrogen atom located on a nitrogen atom in these groups is replaced by an acyl group or carbamate group. Suitable acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for example, the groups R10xe2x80x94COxe2x80x94 and R11Oxe2x80x94COxe2x80x94, in which R10 is hydrogen, (C1-C18)-alkyl, (C3-C14)-cycloalkyl, (C3-C14)-cycloalkyl-(C1-C8)-alkyl-, (C5-C14)-aryl, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O, S, or (C5-C14)-aryl-(C1-C8)-aryl-, in which 1 to 5 carbon atoms in the aryl moiety can be replaced by heteroatoms such as N, O, S, and R11 has the meanings indicated for R10 with the exception of hydrogen.
In the compounds of the formula I, the radicals R1 and R2 preferably together are a saturated or unsaturated, in particular a saturated, bivalent (C2-C5)-alkylene radical, in particular a (C2-C4)-alkylene radical, especially a (C2-C3)-alkylene radical, which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl-and oxo, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms can be fused to a carboncarbon bond in the alkylene radical. In the compounds of the formula I, the radicals R1 and R2 are particularly preferably the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2, 3, 4 or 5, preferably the numbers 2, 3 or 4, particularly preferably the numbers 2 or 3, and which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-,(C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the group xe2x80x94(CH2)pxe2x80x94.
R3 is preferably (C1-C4)-alkyl or (C1-C4)-alkoxy.
R4 is preferably hydrogen or unsubstituted or substituted (C1-C6)-alkyl, particularly preferably hydrogen or (C1-C6)-alkyl, which is unsubstituted or substituted by a radical from the group consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94 and NR7R7xe2x80x2, where R7 and R7 xe2x80x2 independently of one another are hydrogen or (C1-C4)-alkyl. R4 is very particularly preferably hydrogen or unsubstituted or substituted (C1-C4)-alkyl, especially preferably hydrogen or (C1-C4)-alkyl which is unsubstituted or substituted by a radical from the group consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94 and NR7R7xe2x80x2, where R7 xe2x80x2 and R7 independently of one another are hydrogen or (C1-C4)-alkyl.
R5 is preferably (C1-C8)-alkyl or a radical of the formula II
in which the radicals R3 can be identical or different and can be located in any desired positions of the phenyl radical, where q is 0, 1 or 2, preferably 0 or 1, particularly preferably 0. R5 is particularly preferably (C1-C4)-alkyl or the radical of the formula II, in which q is 0 or 1, very particularly preferably R5 is the radical of the formula II, in which q is 0 or 1, i.e. an unsubstituted benzyl radical or a benzyl radical monosubstituted in the ortho-position, meta-position or par-aposition by R3.
R6 is preferably hydrogen or (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, particularly preferably hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94, in particular hydrogen.
A is preferably CH2 or O.
Preferred compounds of the formula I are those compounds in which one or more of the radicals have preferred meanings or one specific of the preferred meanings, all combinations of such preferred meanings being a subject of the present invention. Particularly preferred compounds of the formula I are those compounds in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C5)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2, 3, 4 or 5, where the (C2-C5)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C4)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C2-C5)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or C1-C6)-alkyl which is unsubstituted or is substituted by a radical from the group consisting of (C1-C4)-alkoxy, C1-C4)-alkyl-S(O)2xe2x80x94 and NR7R7xe2x80x2, where R7 and R7xe2x80x2 independently of one another are hydrogen or C1-C4)-alkyl;
R5 is (C1-C8)-alkyl or a radical of the formula II
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94;
A is CH2 or 0;
m is 1, 2or 3;
n is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Very particularly preferred compounds of the formula I are those compounds in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C4)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2, 3 or 4, where the (C2-C4)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)aryl, (C6-C4)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C2)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C4)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C6)-alkyl;
R5 is (C1-C4)-alkyl or a radical of the formula II
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is CH2or O;
m is 1, 2or 3;
n is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are those in which:
R1 and R2 together are a saturated or unsaturated bivalent (C2-C3)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2 or 3, where the (C2-C3)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C4)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-remembered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R31, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C2-C3)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is (C1-C4)-alkyl or a radical of the formula II
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is CH2;
m is 1;
n is 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are also those in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C3)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2 or 3, where the (C2-C3)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, C1-C6)-alkyl, C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C4)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C3)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is (C1-C4)-alkyl or a radical of the formula II
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is oxygen;
m is 1;
n is 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are furthermore those in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C3)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2 or 3, where the (C2-C3)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6) alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C3)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or C1-C4)-alkyl;
R5 is C1-C4)-alkyl or a radical of the formula II
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is oxygen;
m is 3;
n is 0;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Particularly especially preferred compounds of the formula I are those in which
R1 and R2 together are a saturated bivalent (C2-C3)-alkylene radical which is unsubstituted, in particular together are the unsubstituted group xe2x80x94(CH2)2xe2x80x94 or the unsubstituted group xe2x80x94(CH2)3xe2x80x94;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is unsubstituted benzyl;
R6 is hydrogen;
A is oxygen;
m is 3;
n is 0;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Preferred compounds of the formula I are additionally those in which the carbon atom to which the two groups R4Oxe2x80x94COxe2x80x94 and R5OCOxe2x80x94NHxe2x80x94 are bonded has the S configuration.
The present invention also relates to processes for the preparation of the compounds of the formula I. The compounds can generally be prepared, for example in the course of a convergent synthesis, by linkage of two or more fragments which can be derived retrosynthetically from the formula I. In the preparation of the compounds of the formula I it can generally be advantageous or necessary in the course of the synthesis to introduce functional groups which could lead to undesired reactions or side reactions in the respective synthesis step, in the form of precursors which are later converted into the desired functional groups, or temporarily to block functional groups by a protective group strategy suited to the synthesis problem, which is known to those skilled in the art (Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991).
Thus the compounds of the formula I can be prepared, for example, by linking in a manner known per se a carboxylic acid or carboxylic acid derivative of the
in which R4, R5, A, n and m are defined as indicated for the formula I, or alternatively functional groups can be present in the form of precursors which are later converted into the groups present in the compounds of the formula I, or functional groups are present in protected form, and in which X is a nucleophilically substitutable leaving group, with a guanidine or guanidine derivative of the formula IV
in which R1, R2 and R6 are defined as indicated for the formula I, or alternatively functional groups can be present in the form of precursors which are later converted into the groups present in the compounds of the formula I, or functional groups are present in protected form.
The group COX in the formula III is preferably the carboxylic acid group COOH or an activated carboxylic acid derivative. X, for example, is hydroxyl or halogen, in particular chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryloxy, for example phenoxy, pentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a radical of a nitrogen heterocycle bonded via a nitrogen atom, in particular of an azole, such as, for example, 1-imidazolyl. X can furthermore be, for example, ((C1-C4)-alkyl)xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94 or tolylsulfonyloxy and the activated acid derivative can thus be a mixed anhydride.
If X is hydroxyl, i.e. if the guanidine of the formula IV is reacted with a carboxylic acid, then the carboxylic acid is expediently first activated. The activation can be carried out, for example, with dicyclohexylcarbodiimide (DCCl) or with O-((cyano(ethoxycarbonyl)-methylen)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU; Kxc3x6nig et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Escom, Leiden 1991, p. 143) or other activating reagents customary in peptide chemistry.
Beside the free guanidines of the formula IV, guanidinium salts can also be employed in the reaction with the compounds of the formula III, from which the free guanidines are then prepared in situ or in a separate step by means of a base. The reaction of an activated carboxylic acid derivative of the formula III with the guanidine (derivate) of the formula IV is preferably carried out in a manner known per se in a protic or aprotic polar, but inert, organic solvent. In this case, methanol, isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran at temperatures from 0xc2x0 C. up to the boiling temperature of these solvents have proven suitable, for example, in the reaction of the methyl esters (X=methoxy) or of the ethyl esters (X=ethoxy) with the guanidines. The reactions of compounds of the type COX with salt-free guanidines are advantageously carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate with addition of a base such as, for example, potassium tert-butoxide or sodium methoxide. However, water can also be used as a solvent in the reaction of compounds of the formula III with guanidines, for example when using a base such as sodium hdyroxide. If X is chlorine, the reaction is advantageously carried out with addition of an acid scavenger, for example of an added base or in the presence of excess guanidine (derivative) for binding the resulting hydrohalic acid. The reaction mixture is worked up and, if desired, the reaction product is then purified by the customary processes familiar to those skilled in the art.
Protective groups optionally still present in the products obtained from the compounds of the formulae III and IV are then removed by standard processes, for example tert-butyl ester groups are converted into the carboxylic acid groups by treatment with trifluoroacetic acid, benzyl groups are removed by hydrogenation or fluorenylmethoxycarbonyl groups are removed by secondary amines, and further reactions are carried out by standard processes, for example acylation reactions. If appropriate, conversion into physiologically tolerable salts or prodrugs can then be carried out by known processes.
The starting components of the formulae III and IV, which are linked to give the acylguanidine derivatives of the formula I, are commercially available or can be prepared by or analogously to processes described in the literature. The preparation of the starting components of the formula III is illustrated by way of example in the following schemes, the present invention not being restricted to these syntheses or these starting components. It does not cause any problems to those skilled in the art to carry out the modifications of the syntheses shown, which are necessary for the preparation of other compounds according to the invention.
Thus the carboxybenzaldehyde of the formula V can be reacted, for example in the presence of pyridine and piperidine, with the malonic acid ester salt of the formula VI to give the cinnamic acid derivative of the formula VII which, after hydrogenation, for example in the presence of palladium on carbon, to give the compound of the formula VII and activation of the carboxylic acid group, can be condensed with the 2,3-diaminopropionic acid derivative of the formula IX to give the compound of the formula X (Scheme 1). The condensation can be carried out, for example, in the presence of TOTU or another customary activating agent for carboxylic acids. In the formula X, Z is the benzyloxycarbonyl group, but instead of Z other groups can be present on the nitrogen atom which either only temporarily protect the amino group in the 2-position or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Likewise, instead of the tert-butyl ester, other esters can be present which either only temporarily protect the acid group or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Compounds analogous to the compound of the formula VII can also be obtained by other processes for the conversion of a carbonyl group into an alkene, for example by a Wittig reaction.
The p-hydroxybenzoic acid of the formula XI can be condensed with the 2,3-diaminopropionic acid derivative of the formula IX to give the compound of the formula XII, the above explanations applying for the compound of the formula IX and the condensation. The compound of the formula XII can be alkylated with halocarboxylic acid derivatives under standard conditions, for example with the bromoacetic acid ester of the formula XIII to give the compound of the formula XIV (Scheme 2). p-Aminobenzoic acid and p-mercaptobenzoic acid can be reacted correspondingly.
The tyrosine derivative of the formula XV can be alkylated under standard conditions with halocarboxylic acid derivatives, for example with the bromobutyric acid ester of the formula XVI to give the compound of the formula XVII (Scheme 3). In the formula XV, Z is the benzyloxycarbonyl group, but instead of Z other groups can be present on the nitrogen atom, which either only temporarily protect the amino group or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Likewise, instead of the tert-butyl ester, other esters can be present which either only temporarily protect the acid group or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Analogs of the compounds of the formula XVII can be prepared correspondingly or analogously to the above preparation processes.
The compounds of the formulae X, XIV and XVII are examples of compounds of the formula III in which X is methoxy or ethoxy. These compounds and analogous compounds which are obtained from the syntheses described above containing a group which is an activated carboxylic acid derivative can be reacted directly with the compounds of the formula IV. The compounds obtained in the above syntheses, however, can also first be converted under standard conditions by cleavage of the methyl ester group or ethyl ester group or another ester group present in the position concerned in the compounds of the formulae X, XIV and XVII into the corresponding carboxylic acids, which are then reacted with the guanidines of the formula IV after in situ activation, for example with TOTU or DCCl, or after conversion into an activated carboxylic acid derivative. If, as activated acid derivatives, it is intended to prepare, for example, the carboxylic acid chlorides (formula III, X=Cl), this can be carried out, for example, using thionyl chloride. If it is intended to prepare, for example, the methyl esters (X=methoxy) from the carboxylic acids, this can be carried out by treating with gaseous hydrogen chloride in methanol. Other activated acid derivatives can be prepared in a manner known per se from the carboxylic acid chlorides or directly from the carboxylic acids on which they are based (X=OH), for example the imidazolides (X=1-imidazolyl) by treating the acids with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)) or the mixed anhydrides, for example by reaction with chloroformic acid esters such as ethyl chloroformate or with tosyl chloride in the presence of amines such as triethylamine in an inert solvent. A number of suitable methods for the preparation of activated carboxylic acid derivatives are indicated with details of source literature in J. March, Advanced Organic Chemistry, Third Edition, John Wiley and Sons, 1985, p. 350.
The compounds of the formula I are valuable pharmaceutical active ingredients which are suitable, for example, for the therapy and prophylaxis of bone disorders, tumor diseases or cardiovascular disorders. The compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral administration and which contain, in addition to customary pharmaceutically innocuous carriers and/or additives, an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs as active constituent.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for use as pharmaceuticals, to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the production of pharmaceuticals for the therapy and prophylaxis of the diseases mentioned above or below, for example for the therapy and prophylaxis of bone disorders or tumor diseases, and also to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the therapy and prophylaxis of these diseases. The present invention furthermore relates to pharmaceutical preparations which contain an efficacious amount of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with a customary pharmaceutically innocuous carrier.
The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topical, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se, one or more pharmaceutically inert inorganic and/or organic carriers being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, 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 production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs. The amount of the active ingredient(s) of the formula I and/or its (their) physiologically tolerable salts and/or its(their) prodrugs in the pharmaceutical preparations normally is 0.2 to 500 mg, preferably 1 to 200 mg.
In addition to the active ingredients and carriers, the pharmaceutical preparations can additionally contain one or more additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, and also solvents or solubilizers or agents for achieving a depot effect, and also salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs, they can also contain one or more other therapeutically or prophylactically active ingredients.
The compounds of the formula I are antagonists of the vitronectin receptor and have, for example, the ability to inhibit the binding of osteoclasts to the bone surface and thereby bone resorption by osteoclasts. The action of the compounds of the formula I can be demonstrated, for example, in an assay in which the inhibition of the binding of vitronectin to cells which contain the vitronectin receptor is determined. Details of such an assay are given below. As vitronectin receptor antagonists, the compounds of the formula I and their physiologically tolerable salts and their prodrugs are generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell interaction processes or cell-matrix interaction processes, or which can be influenced by an inhibition of interactions of this type, or for their prevention, alleviation or cure an inhibition of interactions of this type is desired. As explained at the beginning, such interactions, for example, play a part in bone resorption, in angiogenesis or in the proliferation of cells of the vascular smooth musculature. The compounds of the formula I and their physiologically tolerable salts and their prodrugs are therefore suitable, for example, for the alleviation or cure of diseases which are caused at least partially by an undesired extent of bone resorption, angiogenesis or proliferation of cells of the vascular smooth musculature.
Bone diseases for whose treatment and prevention the compounds of the formula I according to the invention can be employed are especially osteoporosis, hypercalcemia, osteopenia, for example caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget""s disease. In addition, the compounds of the formula I can be used for the allevation, avoidance or therapy of bone disorders which are caused by a glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by bone loss, which is based on the inequilibrium between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts. The compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used as inhibitor of bone resorption, for example in the therapy or prophylaxis of osteoporosis, in combination with conventional osteoporosis treatments, for example in combination with bisphosphonates, estrogens, estrogen/progesterone, estrogen agonists/antagonists, calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride. Administration of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and of other active ingredients effective in the treatment or prophylaxis of osteoporosis like those listed before can take place simultaneously or sequentially, in any order, and jointly or separately. For use in such a combination treatment or prophylaxis the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and one or more other active ingredients like those listed before can together be present in a single pharmaceutical preparation, for example tablets or granules, or can be present in two or more separate pharmaceutical preparations which can be contained in a single package or in two or more separate packages. The use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs in such a combination therapy or prophylaxis and their use in the production of pharmaceuticals for such a combination therapy or prophylaxis are also covered by the present invention. The invention furthermore relates to pharmaceutical preparations which comprise efficacious amounts of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with at least one other active ingredient effective in the treatment. or prophylaxis of osteoporosis or in the inhibition of bone resorption like those listed before, together with a customary pharmaceutically innocuous carrier. The above explanations on pharmaceutical preparations correspondingly apply to such pharmaceutical combination preparations. Apart from use as inhibitors of bone resorption by osteoclasts, the compounds of the formula I and their physiologically tolerable salts and their prodrugs are used as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the therapy or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, or for the therapy or prophylaxis of nephropathies or retinopathies, such as, for example, diabetic retinopathy. As inhibitors of tumor growth or tumor metastasis the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used in combination with conventional cancer therapy. Examples of conventional cancer therapy are given in Bertino (Editor), Encyclopedia of Cancer, Academic Press, 1997. All the above statements relating to the use of the compounds of formula I in combination with conventional osteoporosis therapy like, for example, possible modes of administration and pharmaceutical combination preparations, correspondingly apply to the use of the compounds of formula I in combination with conventional cancer therapy.
When using the compounds of the formula I, the dose can vary within wide limits and, as is customary, is to be suited to the individual conditions in each individual case. It depends, for example, on the compound employed which can be physiologically active by itself or can be a prodrug that is first metabolically activated, or on the nature and severity of the disease to be treated, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out. In the case of oral administration, the daily dose is in general 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, in particular 0.1 to 5 mg/kg, for example 0.3 to 0.5 mg/kg, to achieve effective results in an adult weighing about 75 kg (in each case in mg per kg of body weight). Also in the case of intravenous administration the daily dose is in general approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg (in each case per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated.
Apart from use as pharmaceutical active ingredients, the compounds of the formula I can also be used as vehicles or carriers of active ingredients in order to transport the active ingredient specifically to the site of action (=drug targeting; see, for example, Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, Ed. Born, G. V. R. et al., Springer Verlag). The active ingredients to be transported are in particular those which can be used for the treatment of the abovementioned diseases.
The compounds of the formula I and their salts can furthermore be employed for diagnostic purposes, for example in in vitro diagnoses of cell or tissue samples, and as auxiliaries in biochemical investigations in which blocking of the vitronectin receptor or influencing of cell-cell or cell-matrix interactions is desired. They can furthermore be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by modification or introduction of substituents or functional groups.

Acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists


A showcase is described. The showcase has at least a vertical side wall with an inner face and an outer face, and at least a horizontal upper wall, with a lower face and an upper face. The side and upper walls are both made of a transparent material and are fixedly fastened to one another at respective edges; the edges of the side and upper walls are shaped so as to comprise respective contact bands facing one another and glued to one another. The contact bands have two horizontal contact bands, one on the edge of the side wall, the other on the edge of the upper wall, and extending between an inner bound and an outer bound, wherein the outer bound is internal with respect to the outer face of the side wall. The upper wall rests horizontally on the side wall and the weight of the upper wall weighs directly on the side wall, without stressing the adhesive with which they are glued, ensuring the safety of the showcase; furthermore, the junction line between the walls is not visible on the side wall, since the outer bound of the contact bands does not reach the outer face of the side wall.

Showcases of this type must therefore meet requirements of various types, in relation to the preservation and integrity of the exhibits. Moreover, of course, these showcases have to ensure the best visibility for the exhibits.
Systems for making fixed parts integral to one another are therefore very important, so as to ensure the necessary strength to the showcase.
In order to improve visibility, showcase manufacturers seek where possible to use transparent materials—typically glass—for the showcase walls. In addition to ensuring better visibility of the exhibits, the extensive use of glass is often desired by showcase designers since the transparency of the material allows giving maximum emphasis to the exhibits.
Therefore, showcases have been developed with a base surmounted by a case formed by walls; the base accommodates all the necessary technical components to ensure that the environment within the case is protected and is thus normally closed by metal walls, which conceal all technical components from view; vice versa, the case walls are totally or partly made of glass for the above reasons. The technical components can also be accommodated in compartments extending vertically, especially in the case of showcases leaning on walls.
The case may be made of transparent material walls all integral to one another, so as to form a bell that is lifted from the base to access inside the showcase. Or, some walls (fixed walls) are integral to the base and to one another while one or more walls (opening walls) are movable, thanks to suitable opening mechanisms.
In order to make the fixed walls of transparent material integral to one another, it is normal to bond the walls to one another by means of suitable adhesives, along adjacent peripheral edges, often cut at 45°; these junctions are also known as miter-square junctions.
Thanks to modern adhesives, it is possible to ensure good stability and safety of bonding. However, it is sometimes possible that abnormal, unpredictable or unforeseen conditions may lead to a bonding strength lower than expected. This can happen for example because some abnormal and not necessarily detectable condition has occurred in the bonding step which can lead (immediately or maybe later) to a reduction of the adhesion between the glued parts. Or, it may happen that particular environmental conditions (in terms of temperature, humidity and exposure to light or to atmospheric agents) may change—worsening them—the adhesion features of a bonding over time, despite it was made to perfection.
In these cases, the showcase will be exposed to the risk of detachment between the walls, and thus of collapse. This is a risk that occurs mostly in the bonding between a vertical wall and the horizontal upper wall (ceiling), where the weight of the horizontal wall is relieved on the vertical wall through the adhesive, stressing it: in case of failure of the adhesive, the collapse of the horizontal wall right on the works in the showcase at the time of the collapse is immediate and inevitable. Clearly, therefore, it is a risk that, while minimum, should be absolutely avoided: in this case, in fact, instead of protecting the works on display, the showcase would be a hazard itself.
Also, in any case, even the best adhesives have a decay of their grip over time and therefore are only guaranteed for a limited time; when this time limit is reached, replacing the showcase is inevitable, although apparently still intact.
However, in the cases where it is desired to exclude any risks without giving up a showcase with transparent walls, cutting the edges to 45° is usually given up, especially for bonding together a vertical wall and the horizontal upper wall: the latter is glued on top of the vertical wall, leaving the edges simply straight, at 90° with respect to the faces of the walls; these junctions are also known as juxtaposed junctions. In this case, the weight of the horizontal upper wall does not stress the adhesive, reducing the risk of failure; moreover, when failure occurs, the horizontal upper wall is still resting on the vertical wall and therefore does not collapse on the works contained in the showcase.
However, while in a showcase in which the walls are joined at 45° the junction line between the walls is located at the geometrical edge of the of the showcase and is therefore substantially invisible to the observer, in a showcase in which the walls are joined at 90° the junction line between the vertical wall and the horizontal wall is lower than the geometrical edge of the showcase by a distance equal to the thickness of the horizontal upper wall. In this position, the junction line between the walls is clearly visible and can therefore constitute a disturbance to the viewing of the exhibits.
Therefore, there is the problem of totally preventing the risk of collapse of a showcase with glued walls but without introducing any visible elements that may disturb the viewing of the exhibits.

Showcase having shaped and glued wall made of a transparent material


An IC element 2 having an oscillation circuit and an amplification circuit is mounted on a wiring board 1, the IC element 2 is covered with a sealing resin layer 4 having a window 4a on an upper surface of the IC element 2, and a shielding layer 5 is made to adhere to the sealing resin layer 4 and the window 4a from above. In a simple configuration, the entrance of electromagnetic waves into the IC element 2 is reduced, which allows a transmission signal from the IC element 2 to be stabilized.

Conventionally, electronic component modules for outputting signals for transmission, which are used for radio communication or the like, have been used.
Known as an example of such conventional electronic component modules has been one in which a flip-chip mounting-type IC element is mounted on a wiring board, and a sealing resin layer covering the IC element is formed from above (see Patent Document 1).
The electronic component module has an oscillation circuit and an amplification circuit, and oscillates a reference signal using the oscillation circuit, mixes a data signal with the reference signal, amplifies a mixture obtained using the amplification circuit, and outputs a signal for transmission. Small-sized radio communications equipment that can be mounted on personal computers, portable information equipment, and so forth is configured by connecting antennas, transmitting/receiving circuits, and so forth to such electronic component modules.
Patent Document 1: Japanese Unexamined Patent Publication No. 2000-243882

Electronic component module and radio comunications equipment


An electrical connector assembly includes an electrical connector and a complementary connector mated with the electrical connector. The electrical connector includes a shell and a terminal module received in the shell. The shell defining a mating portion extending forwardly and a receiving room recessed from the rear face thereof. The mating portion defines a mating face at a side surface thereof. The terminal module includes an insulator and a plurality of first terminals retained in the insulator. The insulator defines a first face and a second face opposite to the first face. The first terminals includes contacting portions protruding from the first face of the insulator. A supporting plate is inserted between the second face of the insulator and an inner surface of the receiving room and pushing the contacting portions of the first terminals exposed to the mating face.

1. Field of the Invention
The present invention generally relates to an electrical connector assembly and an assembly method of the connector, and more particularly to an electrical connector assembly with a supporting plate.
2. Description of Related Art
A patent publication application No. 201214899 in Taiwan discloses an electrical connector. The electrical connector includes a metal shell and a terminal module retained in an insulative housing. The metal shell defines a mating portion extending forwardly and a receiving room recessed from the rear face thereof. The mating portion defines a mating face which has a cutout thereof. The terminal module includes an insulator assembled into the receiving room from the rear face of the metal shell and a plurality of conductive terminals retained in the insulator. Contacting portions of the conductive terminals extend outwardly beyond the cutout and expose to the mating face. After the terminal module is assembled into the receiving room, plastic material is poured into the cutout to seal gaps between the insulator and the terminal module. However, the pouring of the plastic material might push the terminal module offset a right position or if the terminal module is disposed at an offset position, the plastic material will coat on the contacting portions of the conductive terminals, which results to a bad property of contacting of the conductive terminals.
In view of the foregoing, an electrical connector assembly with a supporting plate and the assembly method thereof would be desirable.

Electrical connector assembly with a supporting plate and assembly method of the same


A combined information display and information input device comprising a matrix of independently addressable light emitting devices and a plurality of light sensing devices, the light emitting devices comprising organic light emitting diodes comprising organic light emitting material positioned between a low work function electrode and a high work function electrode characterized in that the light sensing devices comprise organic photovoltaic devices comprising at least an organic electron donor and at least an organic electron acceptor positioned between a high work function electrode and a low work function electrode. The combined information display and information input device has application as a touch screen, for example for a mobile communication device.

1. Field of the Disclosure
The disclosures relates to a device, which enables both the display of information and the input of information. The device combines light emitting elements to provide an information display function and light sensing elements to provide an information-input function. In particular the disclosure relates to a combined information display and information input device based on organic materials wherein an organic light emitting material is used to provide the light emitting function and an organic light sensing material is used to provide the light sensing function. Methods of manufacture of such devices are also the subject of the disclosure.
2. Brief Description of the Prior Art
Apparatus capable of both displaying information and allowing the input of information are known with the most well established technologies operating by means of a touch sensitive panel or film applied over the surface of a standard display such as a backlit LCD or a CRT display. Such displays have the disadvantage that the introduction of a further component beyond those of the display itself adds to the complexity of manufacturing. In addition wear caused to the touch panel by regular contact limits the durability of this component and contact with the surface of the screen may cause distortion of the image displayed.
A number of efforts have been directed at integrating information display and information input functions onto a single substrate and thereby simplifying the manufacture of the displays. To date most of these efforts have been directed at the combination of LCD technology and inorganic semiconductor photosensor technology. The advantage of using photosensors rather than touch sensors is that no contact with the screen Is needed to input information.
The 1990s saw the growth of a display technology based on organic light emitting materials. Light emitting devices based on organic light emitting materials fall into two broad classes, those based on polymeric light emitting materials, as disclosed in WO 90/13148, and those devices based on low molecular weight light emitting materials, so called small molecules, such as disclosed in U.S. Pat. No. 4,530,507. At around the same time it was appreciated that the same semiconductive organic materials which provide the light emitting material in organic light emitting devices could also be used to detect light, see in particular the disclosure of the light sensing properties of light emitting polymers in U.S. Pat. Nos. 5,331,183 and 5,523,555.
It has been proposed to use this dual operating function of light emitting polymers to provide a device capable of both the display and the input of information. U.S. Pat. No. 5,929,845 discloses a scanner based on a matrix of organic light emitting devices with the devices emitting light onto the surface of the image to be scanned, light reflected from this image is detected by the display allowing information about the scanned image to be stored in a suitable information storage means and if desired displayed by means of the matrix of light emitting devices. This scanner device comprises a single matrix of light emitting polymer devices with each device functioning as both a light emitter and a light detector. U.S. Pat. No. 5,504,323 also suggests using a single matrix of organic light emitting devices with each device acting as both light emitter and light detector. GB2315594 discloses a scanning device where organic light emitting devices are used to provide a light source, light from which is reflected from the image to be scanned, this reflected light is detected by light emitting polymer based sensors.
In these prior art displays the organic electronic devices are used to provide both a light emitting function, when forward biased, and a light detecting function, when reverse biased. The disadvantage of such an arrangement is that the organic electronic devices cannot be optimised to perform both functions therefore any improvement in the light sensing property of the device will generally be detrimental to the light emitting property of the device and vice versa. Such devices can then not operate optimally as both right emitting devices and light sensing devices. Further the need to operate the organic electronic devices alternately in two modes requires complex electronic driving circuitry.

Combined information display and information input device


A tiered device driver system includes a SCSI generic device driver (SGDD) in one tier and one or more SCSI device-class drivers (SDCD) in another tier. In response to a request to access a SCSI device, the operating system creates a request packet that is passed to the appropriate SDCD. Such SDCD creates a generic request packet and associated data structures that contain information specific to the SCSI device being accessed. The generic request packet is passed on to a SCSI generic device driver (SGDD) that creates a SCSI ABIOS request block which it transmits to a SCSI adapter for accessing the desired SCSI device. The SGDD provides functions common to the SDCDs.

By way of background, device drivers are programs or routines which control or manage the flow of data to and from I/O devices. The drivers form part of and interact with other portions of an operating system. An operating system normally includes a basic set of device drivers for I/O devices, such as a keyboard, fixed and floppy disks, display, and printer, commonly used in a personal computer. When an I/O device is added to a data processing system, and such device is not operable under an existing driver, a new driver must be added to the system in order to use the device. Such new driver is customarily supplied by the maker of the I/O device and is installed in the system in accordance with procedures established by the operating system. In personal computers operating with IBM DOS or OS/2 operating systems, such drivers are installed, when the computers are started or rebooted, using commands or instructions in a CONFIG.SYS file.
The high performance models of the IBM PS/2 personal computers include a bus designed in accordance with Micro Channel architecture. (IBM, OS/2, PS/2 and Micro Channel are trademarks of International Business Machines Corporation). Such bus is referred to hereinafter as an "IMC bus" and provides the means by which additional I/O devices and subsystems can be connected to the personal computers. A SCSI (Small Computer System Interface) bus is a bus designed in accordance with SCSI architecture, and provides a standardized design for the attachment thereto of I/O devices known as SCSI devices, that is, devices specifically designed for attachment to a SCSI bus. Such architecture defines a SCSI command set for accessing the devices. Recently, a SCSI adapter and SCSI ABIOS (advanced basic input/output operating system) were developed which allow SCSI devices to be connected to PS/2 computers through the MC bus, and this has created some difficulties or problems which the present invention overcomes.
First, the basic OS/2 drivers for common (non-SCSI) I/O devices cannot be used with SCSI devices, and a driver written for use with one type of operating system cannot be used with another type. Accordingly, the makers of SCSI devices are faced with the prospect of having to write multiple drivers, one for each type of operating system for which they expect to market a SCSI device. A complete driver is relatively complex and commonly requires many programmer months to develop. This can add up to a substantial development effort if several devices must be supported under different operating systems, and it may delay the general availability and widespread use of SCSI devices. The invention, as described in greater detail below, has an objective of simplifying the driver to be provided by a maker or supplier of SCSI devices for use in a data processing system programmed to operate under OS/2 operating system. Simplification makes it easier and cheaper to develop and supply such drivers. This objective is accomplished by a two tier driver system in which the SCSI developer provides a SCSI driver that is specific to a class of SCSI devices, and the operating system includes a generic SCSI driver having functions commonly used by the specific driver classes. Not only does such system eliminate the need for developers to include common functions but it also hides from the developer the need to program to the relatively complex interface with ABIOS.
Second, PS/2 personal computers include microprocessors that operate in both real mode and protected mode. Bimodal operation provides compatibility with older application programs and allows such microprocessors to run both application programs written for a DOS environment and application programs written for an OS/2 environment. Device drivers are also bimodal so that such drivers and corresponding devices can be used for both DOS and OS/2 application programs. Under OS/2, device drivers are loaded into the low end of physical memory for access by both DOS and OS/2 application programs. The more drivers there are, the more memory space is used thereby limiting the amount of physical memory space used for DOS application programs which run in real mode. Thus, another objective of the invention is to provide a SCSI driver system which efficiently uses memory address space. This objective is also satisfied by having a two tier driver system in which common functions are included in a generic driver. The common functions are used by SCSI device-class drivers and thus avoid the need for each driver to be complete in itself and thereby duplicate functions and waste memory space.

Layered SCSI device driver with error handling circuit providing sense data from device directly to the driver on the occurrence of an error


Novel plant cell signaling genes and gene products are provided. These gene, polypeptide and oligonucleotide sequences are useful in regulating plant phenotype. Moreover, these genes and gene products are useful for expression profiling of plant cell signaling genes. The invention specifically provides polynucleotide and polypeptide sequences isolated from Eucalyptus and Pinus species.

1. Field of the Invention
Sequence Listing
The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety.
The present invention relates generally to the field of plant cell signaling genes and polypeptides encoded by such genes, and the use of such polynucleotide and polypeptide sequences for controlling plant phenotype. The invention specifically provides cell signaling polynucleotide and polypeptide sequences isolated from Eucalyptus and Pinus and sequences related thereto.
2. Background
A. Cell Signaling Genes and Gene Products
Plants progress through set developmental programs throughout the course of their lifetimes. This is particularly evident in embryogenesis and floral development. There are a variety of signal molecules produced by certain cells in the plant to which other cells, particularly in the meristematic regions, are poised to respond. These signal molecules trigger distinct sets of developmental programs at specific times that lead to the formation of, for example, flowers or cotyledons. In addition to the programmed developmental pathways, plants are exposed to a variety of environmental stimuli such as changes in temperature and amount of sunlight, availability of water, wounding from mechanical injury and attack by pathogens. Environmental factors, such as exposure to light, heat, cold, drought, etc., activate the expression of genes and synthesis of proteins and other compounds essential for an appropriate response to the environmental signal and thereby, the healthy development of the plant. These responses, like the developmental pathways, are mediated by signal molecules.
To respond to these signal molecules, plant cells produce surface receptor proteins that serve as sensors, regulators and/or transducers of cell signals. The intracellular transduction of a signal is often transmitted via a phosphorylation cascade of molecules that culminates in the transcription of genes to elicit the appropriate cellular response either for normal development or against environmental challenge.
One major class of receptor proteins is the single-transmembrane family, of which there are several subclasses. These proteins are characterized by three domains: an extracellular signal molecule (or ligand) recognition/binding domain, a single cell membrane-spanning domain and an intracellular signal transduction domain which is usually a protein kinase. Many, but not all, plant single transmembrane proteins belong to the subclass known as receptor-like kinases (RLKs). The intracellular kinase domains of plant RLKs are all serine/threonine protein kinases, while the extracellular domains of RLKs are of different types. One type of RLK is characterized by the presence of the extracellular S-domain, originally described in self-incompatibility-locus glycoproteins that inhibit self-pollination. The S-domain is recognized by an array of ten cysteine residues in combination with other conserved residues. Another class of RLKs has an extracellular domain distinguished by leucine rich repeats (LRR) that are involved in protein-protein interactions. Binding of ligands to the extracellular domain is followed by receptor dimerization, autophosphorylation and the activation of a series of intracellular proteins which serve to transduce the signal to the nucleus. The structure of plant RLKs is very similar to receptors found in cell signaling pathways in animal systems.
One example of a plant RLK is the Xa21 gene, which confers resistance to the plant pathogen Xanthomonas oryzae pv. oryzae race 6. This gene was cloned using genetic means comparing Xanthomonas-sensitive and resistant strains of rice (Song et al., Science 270:1804-1806 (1995)), and has been subsequently been shown to confer resistance to Xanthomonas in Arabidopsis. The 1025 amino acid protein possesses a number of features with similarity to known protein domains including a NH2-terminal 23 amino acid residue signal peptide, indicating that the protein is directed to the plasma membrane. Amino acids 81 to 634 contain 23 imperfect copies of a 24-amino acid LRR. Amino acids 651 to 676 encode a 26-amino acid hydrophobic segment that is likely to form a membrane-spanning domain. The C-terminal amino acids contain a putative intracellular serine threonine kinase domain carrying 11 subdomains with all 15 invariant amino acids that are typical of protein kinases. Subdomains VI and VIII are indicative of serine-threonine phosphorylation specificity. Xa21 has strong similarities to other RLKs, such as the Arabidopsis receptor-like kinase proteins RLK5 and TMK1, showing conservation of both the LRR and protein kinase domains. It is not yet known to what protein Xa21 transduces its pathogen recognition signal.
Another kind of membrane receptor molecule expressed by plant cells is histidine kinases (HKs). HKs have been known for some time in bacterial signal transduction systems, where they form one half of a two-component signaling system. The bacterial HK serves as a sensor molecule for extracellular signals, such as changes in osmoticum, nutrients and toxins. The HK autophosphorylates on a histidine residue in response to ligand binding. This phosphohistidine donates its phosphate group to an aspartate residue of the second member of the two component system, known as the response regulator (RR). The phosphorylated RR then binds DNA in a sequence-specific manner, serving to directly activate specific genes which code for proteins that mediate the response to the extracellular stimulus.
Like bacteria, plant cells have a two-component signaling system which consists of a sensor element HK and a RR. The two components may be separate molecules or may exist as a hybrid molecule (hereinafter referred to as hybrid HK/RR proteins). The HK proteins are distinguished by well-conserved amino acid motifs that occur in a specific order. From the amino terminus, the conserved regions are identified as the H, N, G1, F and G2 boxes. These motifs are usually found within a 200-250 amino acid span of the protein. The G1, F and G2 boxes are thought to be involved in nucleotide binding. As in bacteria, upon receiving the extracellular signal, the HK is autophosphorylated on the histidine residue contained in the H box. The phosphate group is subsequently transferred to the RR. All HKs are believed to phosphorylate a RR, as an obligate part of signal transduction. RRs are characterized by the absolute conservation of an aspartate which is phosphorylated by the phosphohistidine of the HK, and a conserved lysine residue. Unlike bacteria, RRs in plants have not been shown to bind DNA directly. Rather, the plant RRs characterized to date appear to transduce the signal into protein kinase cascades, which eventually phosphorylate and activate or inactivate transcription factors, and thereby affect gene expression.
The ethylene receptor (ETR1; Chang et al. Science 262:539-544) is the best known two-component signaling system in plants. Ethylene is a well known signal molecule that is involved in the regulation of plant development as well as the coordination of fertilization, senescence, skoto/photomorphogenesis and responses to pathogens and mechanical injury. The ethylene receptor is a hybrid HK/RR protein. The signal is transduced through a Raf-like protein kinase named CTR1. CTR1 is a negative regulator of downstream steps in the signaling pathway. While the details of this pathway remain unclear, it appears that the HK is constitutively active in the absence of ethylene, thereby constantly phosphorylating CTR1, which in turn represses other genes in the ethylene response pathway. Binding of ethylene to ETR1 inhibits the HK function of the receptor, resulting in the inhibition of the negative regulator CTR1, thereby allowing the activation of downstream proteins in the ethylene signal transduction cascade. This culminates in activation of ethylene response genes.
More recently, two RR genes, IBC6 and IBC7, which are induced in response to the plant growth regulator cytokinin, have been cloned from Arabidopsis thaliana and characterized (Brandstatter and Kieber, The Plant Cell 10:1009-1019 (1998)). It is likely that IBC6 and IBC7 are involved in the transduction of the cytokinin signal in plants. This is particularly interesting in light of the fact that a gene encoding the hybrid HK/RR protein CKI1 (Kakimoto, Science 274:982-985, 1996) causes cytokinin-like effects when it is ectopically expressed in transgenic plants. Thus it appears likely that a two-component HK/RR system is involved in cytokinin signal transduction. Cytokinin is known to regulate plant growth and development, including such physiological events as nutrient metabolism, expansion and senescence of leaves, and lateral branching.
While polynucleotides encoding proteins involved in plant cell signaling have been isolated for certain species of plants, genes encoding many such proteins have not yet been identified in a wide range of plant species. Thus, there remains a need in the art for materials which may be usefully employed in the modification of cell signaling in plants.
Proper plant growth and development requires the ability to react to environmental and developmental factors. Throughout its life, a plant is subject to changes in light, temperature, water and nutrient availability. Plants are also subject to attack by pathogens, such as viruses, nematodes, mites, and insects. Reacting to developmental and environmental cues requires complex interactions between environmental signals and factors internal to the plant. Such reaction is typically effected by changes in gene expression. Various internal signals are required for coordinating gene expression during development and in response to environmental factors. These internal signals are communicated throughout by signal transduction pathways that allow propagation of the original signal. This ultimately results in the activation or suppression of gene expression.
Plant development is also affected by cell environmental factors such as temperature, nutrient availability, light, etc. See Gastal and Nelon, Plant Physiol. 105:191-7 (1994), Ben-Haj-Sahal and Tardieu, Plant Physiol. 109:861-7 (1995), and Sacks et al., Plant Physiol. 114:519-27 (1997). Plant development and phenotype are affected by cell signaling, and altering expression of the genes involved in the cell signaling can be a useful method of modifying plant development and altering plant phenotype.
The ability to alter expression of cell signaling genes is extremely powerful because cell signaling drives plant development, including growth rates, responses to environmental cues, and resulting plant phenotype. Control of plant cell signaling and phenotypes associated with alteration of cell signaling gene expression has, among others, applications for alteration of wood properties and, in particular, lumber and wood pulp properties. For example, improvements to wood pulp that can be effected by altering cell signaling gene expression include increased or decreased lignin content, increased accessibility of lignin to chemical treatments, improved reactivity of lignin, and increased or decreased cellulose or hemi content. Manipulating the plant signal transduction pathways can also engineer better lumber having increased dimensional stability, increased tensile strength, increased shear strength, increased compression strength, increased shock resistance, increased stiffness, increased or decreased hardness, decreased spirality, decreased shrinkage, and desirable characteristics with respect to weight, density, and specific gravity.
B. Expression Profiling and Microarray Analysis in Plants
The multigenic control of plant phenotype presents difficulties in determining the genes responsible for phenotypic determination. One major obstacle to identifying genes and gene expression differences that contribute to phenotype in plants is the difficulty with which the expression of more than a handful of genes can be studied concurrently. Another difficulty in identifying and understanding gene expression and the interrelationship of the genes that contribute to plant phenotype is the high degree of sensitivity to the environmental factors that plants demonstrate.
There have been recent advances using genome-wide expression profiling. In particular, the use of DNA microarrays has been useful to examine the expression of a large number of genes in a single experiment. Several studies of plant gene responses to developmental and environmental stimuli have been conducted using expression profiling. For example, microarray analysis was employed to study gene expression during fruit ripening in strawberry, Aharoni et al., Plant Physiol. 129:1019-1031 (2002), wound response in Arabidopsis, Cheong et al., Plant Physiol. 129:661-7 (2002), pathogen response in Arabidopsis, Schenk et al., Proc. Nat'l Acad. Sci. 97:11655-60 (2000), and auxin response in soybean, Thibaud-Nissen et al., Plant Physiol. 132:118. Whetten et al., Plant Mol. Biol. 47:275-91 (2001) discloses expression profiling of cell wall biosynthetic genes in Pinus taeda L. using cDNA probes. Whetten et al. examined genes which were differentially expressed between differentiating juvenile and mature secondary xylem. Additionally, to determine the effect of certain environmental stimuli on gene expression, gene expression in compression wood was compared to normal wood. 156 of the 2300 elements examined showed differential expression. Whetten, supra at 285. Comparison of juvenile wood to mature wood showed 188 elements as differentially expressed. Id. at 286.
Although expression profiling and, in particular, DNA microarrays provide a convenient tool for genome-wide expression analysis, their use has been limited to organisms for which the complete genome sequence or a large cDNA collection is available. See Hertzberg et al., Proc. Nat'l Acad. Sci. 98:14732-7 (2001 a), Hertzberg et al., Plant J. 25:585 (2001b). For example, Whetten, supra, states, "A more complete analysis of this interesting question awaits the completion of a larger set of both pine and poplar ESTs." Whetten et al. at 286. Furthermore, microarrays comprising cDNA or EST probes may not be able to distinguish genes of the same family because of sequence similarities among the genes. That is, cDNAs or ESTs, when used as microarray probes, may bind to more than one gene of the same family.
Methods of manipulating gene expression to yield a plant with a more desirable phenotype would be facilitated by a better understanding of cell signaling gene expression in various types of plant tissue, at different stages of plant development, and upon stimulation by different environmental cues. The ability to control plant architecture and agronomically important traits would be improved by a better understanding of how cell signaling gene expression effects formation of plant tissues, how cell signaling gene expression protects plants from pathogens and adverse environmental conditions, and how plant growth and the cell signaling are connected. Among the large number of genes, the expression of which can change during development of a plant, only a fraction are likely to effect phenotypic changes of agronomic significance.


The techniques disclosed herein enable participants of a teleconference session to access the functionality of a number of task-related program modules while maintaining engagement with aspects of a teleconference session within a single user interface. For example, a session participant can access files, various chat discussions, various channels, calendars, emails, an operating system desktop, and other functionality of a computing device while viewing one or more video streams of a teleconference session within a unified graphical user interface. The session participant can maintain engagement with both audio and video capabilities while performing tasks, including but not limited to, selecting, viewing, and modifying content data. In some configurations, a specialized graphical user interface allows a user to view one or more video streams of the teleconference session in predetermined positions while also providing optimal access to tools for interacting with different types of content managed by a variety of modules.

Communication and collaboration are key aspects in people's lives, both socially and in business. Communication and collaboration tools have been developed with the aim of connecting people to share experiences. In many cases, the aim of these tools is to provide, over a network, an experience which mirrors real life interaction between individuals and groups of people. Interaction is typically provided by audio and/or visual elements.
Such tools include instant messaging, voice calls, video calls, group chat, shared desktop, shared media and content, shared applications, etc. Such tools can perform capture, manipulation, transmission and reproduction of audio and visual elements, and use various combinations of such elements in an attempt to provide a collaborative environment. A user can access such tools to create a teleconference session with multiple users by the use of a laptop or desktop computer, mobile phone, tablet, games console, etc. Such devices can be linked in a variety of possible network architectures, such as peer-to-peer architectures or client-server architectures or a hybrid, such as a centrally managed peer-to-peer architecture.
Some current teleconference technologies can leave much to be desired. For example, in some existing programs, when participants of a teleconference session desire to interact with certain types of content, such as a document or spreadsheet, users often need to open a separate window or a completely different program. This issue also exists when users wish to conduct a private chat session with certain users, particularly when they wish to engage in a private chat session with users that are not participants of a teleconference session. In any arrangement where a user is required to switch to a different window or a completely different program to conduct a task, a participant's attention is diverted from the contents of the teleconference session. While a user is engaged with other user interfaces or other programs, important subject matter communicated in the session may be missed or overlooked. Even worse, such distractions of one participant can reduce the overall engagement of all session participants.
It is with respect to these and other considerations that the disclosure made herein is presented.

Integrated multitasking interface for communication sessions