The invention relates to new sulphonylaminopyrrolidinone compounds having antithrombotic activity which, in particular, inhibit blood clotting factor IXa and/or factor Xa, to processes for their preparation and to use thereof as drugs.

Blood clotting is a process of control of the blood stream essential for the survival of mammals. The process of clotting and the subsequent dissolution of the clot after wound healing has taken place, after vascular damage and can be divided into four phases:                1. The phase of the initiation of the coagulation cascade either after vessels injury or vasoconstriction leads to low amount of thrombin generation;        2. The next phase is the amplification phase where platelets are activated by thrombin. The platelets attach to the site of the vessel wall damage and form a platelet aggregate which is crosslinked by fibrinogen (fibrin). At the meantime, the complexes of clotting factors (tenase and prothrombinase) can form of the surface of activated platelets. The platelets accelerate blood clotting by means of this mechanism;        3. The formation of the thrombus is stabilized by the fibrin network which is formed consecutive to the cleavage of fibrinogen by the large amount of thrombin;        4. After wound healing, the thrombus is dissolved by the action of the key enzyme of the endogenous fibrinolysis system, plasmin.
In a more detailed scenario, the initiation phase can be driven by two alternative pathways: the intrinsic and the extrinsic pathway. These pathways are initiated by different mechanisms, but in the later phase they converge to give a common final path of the clotting cascade starting with the activation of clotting factor X. The activated factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood. The formation of a thrombus on the bottom of a vessel wall abnormality without a wound is commonly described as the result of the intrinsic pathway. Whereas, fibrin clots formation as a response to tissue damage or an injury is the result of the extrinsic pathway. Both pathways comprise a relatively large number of proteins, which are known as clotting factors.
The "extrinsic" pathway is so called because an exogenous agent (i.e., TF) is required for activation of the clotting factors in plasma. The TF:FVIIa complex is the key initiator of the coagulation protease cascade and activates both FIX to FIXa and FX to FXa.
Alternatively, the "intrinsic" pathway is initiated when prekallikrein, high molecular weight kininogen, factor XI and XII bind to a negatively charged surface: it is the contact phase. The result of these processes is the activation of prekallikrein, factor XII, and finally factor XI that leads, in the presence of Ca2+ ions, to the activation of factor IX.
Whatever the initiating pathway, the generation of factor IXa and factor Xa leads to the formation of low amounts of thrombin, which are able to activate the platelets through the cleavage of protease activated receptors and finally the cofactors factor V and factor VIII: it is the start of the amplification phase. Platelet activation plays a major role in the coagulation since it allows the formation of the two complexes which support the amplification phase: the tenase and the prothrombinase complexes. The tenase complex (FVIIIa:FIXa) plays a key role in amplifying the clotting cascade by activating factor X to factor Xa. The prothrombinase complex (FVa:FXa) activates prothrombin to thrombin, which is the central protease of the clotting cascade. Thrombin cleaves fibrinogen into unsoluble fibrin monomers that polymerize. Thrombin also activates the transglutaminase FXIII to FXIIIa that in turn cross-links soluble fibrin monomers into a fibrin matrix that leads to clot stabilization. Finally, the coagulation cascade is regulated by several natural anticoagulants (TFPI, Antithrombin, HCII, Prot C, Prot S . . . ).
Both clotting factor IX and factor X can be activated by means of the intrinsic pathway and the extrinsic pathway. Their activation are thus a central point of intersection between the two pathways of blood clotting. Moreover the activity of factor IXa is intimately linked to the presence of platelet since, after activation, platelets promote tenase complex formation that increases factor IXa activity by a fold of 200 000 (van Dieijen et al, J. Biol. Chem. 1981; 256: 3433-3442), giving it a central role in the rate limiting step of thrombin generation. Given its central role and its interdependency to platelets, we do know that factor IXa has an important role in both venous and arterial thrombosis.
Evidence is given by the fact that defects in factor IXa lead to hemophilia B. More precisely, the clinical phenotype of hemophilia B depends on the plasma FIX level. Thus, spontaneous bleeding occurs in patients with severe hemophilia (<1% FIX activity). Whereas mild FIX deficiency may not require prophylaxis to prevent bleeding during minor procedures, but interestingly, in epidemiological studies it has been associated with fewer cardiovascular events ({hacek over (S)}rárnek A et al, Lancet. 2003; 362: 351-354; Tuinenburg A el al, J Thromb Haemost. 2009; 7: 247-254). In mirror, increased concentrations of factor IXa in the blood lead to a significantly increased risk of thrombosis formation (Weltermann A, et al., J Thromb Haemost. 2003; 1: 28-32). And finally the regulation of factor IXa activity can reduce thrombus formation in animal models (Feuerstein G Z, et al., Thromb Haemost. 1999; 82: 1443-1445).
In conclusion, as described by Eikelboom in his recent review (Arterioscler Thromb Vasc Biol. 2010; 30: 382-7), "the narrow window for clinically important bleeding with a wider window for reduced cardiovascular events in hemophilia B carriers lends further support for FIXa as an attractive target for anticoagulant therapy."
Numerous documents describe compounds with antithrombotic activity.
For instance, the U.S. Pat. No. 6,432,955 B1 is directed to anti-thrombotic compounds all comprising the following core:
which may be linked to a variety of side-chains.
Another example is the U.S. Pat. No. 6,602,864 B1 describing factor Xa inhibitors of formula:
where Z is an alkylenyl group.
The compounds of the formula I according to the invention are suitable for prophylactic and for therapeutic administration to humans who suffer from diseases which accompany thromboses, embolisms, hypercoagulability or fibrotic changes. They can be employed for secondary prevention and are suitable both for acute and for long-term therapy.
The invention therefore relates to a compound corresponding to the formula (I):
                in which:        R1 represents a hydrogen atom, a (C1-C6)alkyl group, a (C3-C7)cycloalkyl group, a (C3-C7)cycloalkyl-(C1-C6)alkyl- group, a Rb—O—Ra— group where Rb represents a (C1-C6)alkyl group or a (C3-C7)cycloalkyl group and Ra represents a (C1-C6)alkyl group, or a Rd-O—C(O)—O-Rc- group where Rd represents a (C1-C6)alkyl group or a (C3-C7)cycloalkyl group and Rc represents a (C1-C6)alkyl group, or a Rf—C(O)—O—Re— group where Re represents a (C1-C6)alkyl group and Rf represents a (C1-C6)alkyl group,        R2 represents a halogen atom, —OH, —CN, or a (C1-C6)alkyl group, or an —O—(C1-C6)alkyl group, said alkyl groups being non-substituted or substituted by one or more halogen atoms, identical to or different from one another, or a Rg-O—Rh—O— group where Rg represents a (C1-C6)alkyl group and Rh represents a (C1-C6)alkyl group,        R2′ represents a hydrogen atom or a (C1-C6)alkyl group,        R3 represents:
                R4 and R5 represent, independently of one another, a (C1-C6) alkyl group or a (C3-C7)cycloalkyl group,        or R4 and R5 together form, with the nitrogen atom to which they are attached, a 3 to 7 membered heterocycloalkyl group comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen and sulphur, said heterocycloalkyl group being non-substituted or substituted by one or more groups, identical or different from one another, chosen from halogen atom and (C1-C6)alkyl group, (C1-C6)alkoxy group, —CF3, —OCF3,        R6 represents a halogen atom, a hydrogen atom, a (C1-C6)alkyl group, a (C1-C6)alkoxy group or —CN.
The compounds of formula (I) comprise at least two asymmetric carbon atoms, identified by the asterisks (*1 and *2) in the formula below. They can thus exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and their mixtures, including racemic mixtures, come within the invention.

The asymmetric carbon identified by the asterisk *1 in the above formula advantageously exhibits the (R) configuration. The asymmetric carbon identified by the asterisk *2 in the above formula advantageously exhibits the (S) configuration.
The compounds of formula (I) can exist in the form of bases or of addition salts with acids or bases. Such addition salts come within the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids or bases but the salts of other acids or bases, for example of use in the purification or isolation of the compounds of formula (I), also come within the invention.
In the context of the present invention:                a halogen atom is understood to mean a fluorine, chlorine, a bromine or an iodine;        a (C1-C6)alkyl group is understood to mean a saturated aliphatic group which comprises from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) and which is linear or branched. Mention may be made, by way of examples, of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like;        a (C3-C7)cycloalkyl group is understood to mean a cyclic alkyl group comprising between 3 and 7 carbon atoms, all the carbon atoms being involved in the cyclic structure. Mention may be made, by way of examples, of the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups, and the like;        a heterocycloalkyl group is understood to mean a cycloalkyl group as defined above additionally comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen and sulphur. Mention may be made, by way of examples, of the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl groups. This heterocycloalkyl group can be substituted, in any position, by one or more (for example by 1 to 3) groups, identical to or different from one another, chosen from halogen atoms and alkyl groups, alcoxy groups, —CF3, —OCF3;        a cycloalkyl-alkyl group is understood to mean a cyclic alkyl group as defined above and linked to an alkyl group as defined above. Mention may be made, by way of examples, of the cyclopropyl-methyl group, cyclopropyl-ethyl group and cyclobutyl-methyl group;        an alkoxy group is understood to mean an —O-alkyl radical where the alkyl group is as defined above;        an alkoxyalkyl group is understood to mean a radical of formula alkyl-O-alkyl, where the alkyl groups, which are identical to or different from one another, are as defined above.
According to the present invention, the following stand out:                the compounds of Formula (IA) in which in formula R3 represents:
or                the compounds of Formula (IB) in which R3 represents:
and/or                the compounds of formula (I), (IA) or (IB) in which R2 represents a —OCF3 group,the other substituents being as defined for the compounds of Formula (I).
In the formula (I), (IA), (IB), the following in particular stand out, or any of their combination:                R1 represents a hydrogen atom, a (C1-C6)alkyl group, a (C3-C7)cycloalkyl group, a (C3-C7)cycloalkyl-(C1-C6)alkyl group, a Rb—O—Ra— group where Rb represents a (C1-C6)alkyl group and Ra represents a (C1-C6)alkyl group, or a Rd-O—C(O)—O-Rc- where Rd represents a (C1-C6)alkyl group or a (C3-C7)cycloalkyl group and Rc represents a (C1-C6)alkyl group, or a Rf—C(O)—O—Re— where Re represents a (C1-C6)alkyl group and Rf represents a (C1-C6)alkyl group, and/or        R2 represents an halogen atom, —OH, —CN, or a (C1-C6)alkyl group, or a —O—(C1-C6)alkyl group, said alkyl groups being non-substituted or substituted by one or more halogen atom, identical to or different from one another, or a Rg-O—Rh—O— group where Rg represents a (C1-C6)alkyl group and Rh represents a (C1-C6)alkyl group, and/or        R2′ represents a hydrogen atom or a (C1-C6)alkyl group, and/or        R3 represents:
                 and/or        R4 and R5 represent, independently of one another, a (C1-C6) alkyl group or a (C3-C7)cycloalkyl group, and/or        or R4 and R5 together form, with the nitrogen atom to which they are attached, a 3 to 7 membered N-heterocycloalkyl group comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen and sulphur, said heterocycloalkyl group being non-substituted or substituted by one or more halogen atoms, and/or        R6 represents a halogen atom, a hydrogen atom, a (C1-C6)alkyl group.
According to the present invention, preference is given to the compounds of formula (I) in which:                R1 represents a hydrogen atom, a methyl, an ethyl, a propyl, an isopropyl, a butyl, an isobutyl, a cyclopentyl, a cyclopropylmethyl, a cyclobutylmethyl, a 2-methoxyethyl, a cyclohexyloxycarbonyloxymethyl, a 1-cyclohexyloxycarbonyl oxymethyl, a 2,2-dimethylpropionyloxymethyl,        R2 represents a chlorine atom, a fluorine atom, —OH, —CN, a methyl, an ethyl, a methoxy, an ethoxy, —CF3, —OCF3, a 2-methoxyethoxy,        R2′ represents a hydrogen atom, a methyl,        R3 represents:
                R4 and R5 represent, independently of one another, a methyl or a cyclobutyl,        or R4 and R5 together form, with the nitrogen atom to which they are attached, a heterocycloalkyl group chosen from azetidin-1-yl or pyrrolidin-1-yl, said heterocycloalkyl group being non-substituted or substituted by one or two fluorine atoms,        R6 represents a hydrogen atom, a chlorine atom, a methyl.
According to the present invention, preference is particularly given to the compounds of formula (I) in which:                R1 represents a hydrogen atom or a methyl,        R2 represents a chlorine atom, —CF3, —OCF3,        R2′ represents a hydrogen atom,        R3 represents:
                R4 and R5 represent, independently of one another, a methyl,        or R4 and R5 together form, with the nitrogen atom to which they are attached, a heterocycloalkyl group chosen from azetidin-1-yl or pyrrolidin-1-yl, said heterocycloalkyl group being non-substituted or substituted by one or two fluorine atoms,        R6 represents a hydrogen atom.
Among the compounds according to the invention, mention may in particular be made of the compounds hereinafter:
TABLE IIC 50IC50IUPAC Name generated from(μM)(μM)AutoNom ® (MDL, Elsevier)Chemical StructureIXaXa1(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.14.68 2(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl ester>5>5 3(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester>5ND 4(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.17ND 5(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl esterNDND 6(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.160.20 7(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.112 8(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid isobutyl ester1.600.10 9(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid cyclopropylmethyl ester0.760.029 10(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid cyclobutylmethyl ester1.300.086 11(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid isopropyl ester1.600.021 12 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid cyclopentyl ester1.500.043 13(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester1.600.021 14(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.110.004 15 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid cyclopropylmethyl ester0.780.12 16 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester1.300.074 17 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.0700.017 18(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid ethyl ester2.500.12 19 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid cyclopropylmethyl ester1.101 20(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid isopropyl ester1.500.63 21(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-((R)- 3-fluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.140.008 22(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.150.073 23(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid ethyl ester>51.60 24(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.140.002 25(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester1.100.097 26(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo pyrrolidin-1-yl]-propionic acid0.120.10 27(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo pyrrolidin-1-yl]-propionic acid ethyl esterNDND 28(R)-3-(1-Amino-7-methyl- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.150.034 29(R)-3-(1-Amino-7-methyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.190.15 30(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.150.012 31(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester2.90ND 32(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.180.048 33(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester>5ND 34(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acidND0.032 35(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl esterNDND 36(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.150.47 37(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl esterNDND 38(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acidNDND 39(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid ethyl esterNDND 40(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.100.022 41(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.120.047 42(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.121.20 43(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester0.530.060 44(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.120.014 45(R)-3-(1-Amino-7-ethoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.160.067 46(R)-3-(1-Amino-7-ethoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.130.0084 47(R)-3-(1-Amino-7-ethoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.160.19 48(R)-3-(1-Amino-7-hydroxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acidND0.0064 49(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-{(S)-3-[2- (cyclobutyl-methyl-amino)- thiazole-5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.130.27 50(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.160.005 51(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester1.530.24 52(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl ester2.080.41 53(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.0840.027 54(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid methyl ester1.091.12 55(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid methyl ester0.556.12 56(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid0.0760.56 57(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester2.641.97 58(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.140.035 59(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester2.051.09 60(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.130.034 61(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester5.600.47 62(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.0920.016 63(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.110.042 64(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester0.620.40 65(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid methyl ester3.685.50 66(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.110.19 67(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester0.673.85 (Imax 73%) 68(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.291.91 (Imax 81%) 69(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester>23.85 (Imax 73%) 70(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.270.59 71(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester>2ND 72(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino-5- methyl-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester>25.45 (Imax 71%) 73(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.352.77 (Imax 80%) 74(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino-5- methyl-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.100.81 75(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester>2ND 76(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.230.65 77(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester0.750.11 78(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester1.890.80 79(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.0700.033 80(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-2-oxo-3-(2-pyrrolidin-1-yl- thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid methyl ester2.32, Imax 64%3.23, Imax  63% 81(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-2-oxo-3-(2-pyrrolidin-1-yl- thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid0.0860.37 82(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester2.42, Imax 59%2.43, Imax 69% 83(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.0690.24 84(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester3.59, Imax = 60%0.94 85(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- azetidin-1-yl-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester3.32, Imax = 63% 0.78 86(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(5-chloro-6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester3.1, Imax 50%2.84, Imax 43%  87(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(5-chloro-6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.111.65, Imax 85% 88(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester4.30, Imax 46%3.08, Imax 58% 89(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.190.56 90(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid methyl ester2.05, Imax = 41%ND 91(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid0.122.18, Imax = 68% 92(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- azetidin-1-yl-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.120.019 93(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid butyl ester2.112, Imax = 63%1.0 94(R)-3-(1-Amino-7-cyano- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl ester2.56, Imax = 58%1.06 95(R)-3-(1-Amino-7-cyano- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.0800.025 96(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid0.0830.042 97(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid ethyl esterNDND 98(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid propyl esterNDND 99(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid cyclopropylmethyl esterNDND 100(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid butyl esterNDND 101(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid isopropyl esterNDND 102(R)-3-[1-Amino-7-(2-methoxy- ethoxy)-isoquinolin-6-yl]-2-[(S)- 3-(2-dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester3.800.037 103(R)-3-[1-Amino-7-(2-methoxy- ethoxy)-isoquinolin-6-yl]-2-[(S)- 3-(2-dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.170.0014 104(R)-3-(1-Amino-5-fluoro-3- methyl-isoquinolin-6-yl)-2-[(S)-2- oxo-3-(6-pyrrolidin-1-yl-pyridine- 3-sulfonylamino)-pyrrolidin-1-yl]- propionic acidNDND 105(R)-3-(1-Amino-5-fluoro-3- methyl-isoquinolin-6-yl)-2-[(S)-2- oxo-3-(6-pyrrolidin-1-yl-pyridine- 3-sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl esterNDND 106(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid 2- methoxy-ethyl esterNDND 107(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid 2,2-dimethyl-propionyloxymethyl esterNDND 108(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid 1- cyclohexyloxycarbonyloxy-ethyl esterNDND 109(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid cyclohexyloxycarbonyloxymethyl esterNDND 110(2R)-3-[1-amino-7- (trifluoromethoxy)isoquinolin-6- yl]-2-[(3S)-2-oxo-3-{[(2- pyrrolidin-1-yl-1,3-thiazol-5- yl)sulfonyl]amino}pyrrolidin-1- yl]propionic acid methoxymethyl esterNDNDas well as their enantiomers, diastereoisomers and their mixtures, and the pharmaceutically acceptable salts thereof.
According to a further object, the present invention concerns the process of preparation of the compounds of formula (I) of the invention.
In that which follows, Pg, Pg1 and Pg2 are protective groups. Said protective groups are to be understood to mean a group which makes it possible, on the one hand, to protect a reactive functional group, such as a hydroxyl or an amine, during a synthesis and, on the other hand, to regenerate the reactive functional group intact at the end of the synthesis. Examples of protective groups and also of methods for protection and deprotection are given in "Protective Groups in Organic Synthesis", Green et al., 4th Edition (John Wiley & Sons Inc., New York), 2007.
In accordance with the invention, the compounds of general formula (I) can be prepared according to the process presented in Scheme 1.
In Scheme 1, an aminopyrrolidinone is used as starting material.

The process of the invention of the preparation of a compound of formula (I) may comprise the step of reacting a compound of formula (D):
with a compound of formula R3—SO2-Hal,where R1 is H, alkyl, cycloalkyl or cycloalkylalkyl-, R2, R2′ and R3 are defined as in formula (I) and X represents either H or Pg2, where Pg2 is an amino protective group such as triphenylmethyl (trityl) and Hal is a halogen atom, preferably Cl;optionally followed by:                deprotection of Pg2, where X represents Pg2; and/or        optional hydrolysis of R1 in order to obtain the corresponding compound of formula (I) with R1 being H, this hydrolysis being optionally followed by an esterification with the corresponding R1-Hal where Hal is a halogen atom such as Cl, to obtain the corresponding compounds of formula (I) with alternative R1; or        optional transesterification of R1 with the corresponding R1—OH, in the presence of an alkoxide.
The above esterification may be appropriate in particular to obtain compounds of formula (I) with R1 is Rb—O—Ra—, Rd-O—C(O)—O-Rc- or Rf—C(O)—O—Re—.
The process of the invention may also comprise the further step of isolating the desired compound.
Particular embodiments of the process of the invention are described below.
Particular Embodiment for Step 1a.
The aminopyrrolidinone, for example the (S)-aminopyrrolidinone, the primary amine functional group of which is protected by a group Pg1 (such as a tert-butyl or benzyl carbamate), can be condensed with an alkylpropiolate, a cycloalkylpropiolate or a cycloalkylalkyl-propiolate in order to result in the 2-pyrrolidinoacrylate of structure A, in which R1 represents an alkyl, a cycloalkyl or a cycloalkylalkyl- group (contributed by the alkyl-, cycloalkyl- or cylcoalkylalkyl-propiolate). This reaction is advantageously carried out between 0° C. and 110° C., preferably between 20° C. and 40° C., in the presence of a catalytic amount of a phosphine (such as triphenylphosphine) and in an aprotic solvent, such as tetrahydrofuran (THF), dioxane, toluene or dichloromethane.
Particular Embodiment for Step 2a.
The acrylate of structure A can subsequently react with a 6-halogeno-1-aminoisoquinoline, such as a 6-bromo-1-aminoisoquinoline (which is substituted by a R2 group as defined above), the primary amine functional group of which is protected by a group Pg2, for example a triphenylmethyl (trityl) group, in the presence of a transition metal complex (for example, palladium acetate in combination with a tetraalkylammonium halide hydrate such as tetraethylammonium chloride hydrate), in an aprotic solvent, such as THF, dioxane, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), at a temperature of between 20 and 150° C., to give the compound of 3-(1-aminoisoquinolin-6-yl)-2-pyrrolidinoacrylate type of structure B.
Particular Embodiment for Step 3a.
The derivative B can subsequently be reduced to give the derivative of structure C using hydrogen at a pressure of 1 to 5 bar, at a temperature of between 20 and 100° C., in a protic solvent, such as methanol, ethanol or isopropanol, optionally in combination with an aprotic solvent, such as THF, ethyl acetate or DMF. This hydrogenation can be catalysed by a complex of a transition metal, such as rhodium or ruthenium, with a chiral phosphine, such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) or 1,2-bis(2,5-dimethylphospholano)benzene (DUPHOS), such as (R,R)-(DUPHOS)Rh(COD). The derivative of 3-(1-aminoisoquinolin-6-yl)-2-pyrrolidinopropanoate type of structure C thus obtained has the 2R or 2S configuration according to the enantiomer of the chiral phosphine used.
Particular Embodiment for Step 4a.
The derivative D is subsequently obtained by deprotection of Pg1, by techniques known to a person skilled in the art, of the primary amine functional protective group Pg, present on the pyrrolidinone ring. During this stage, the protective group of the primary amine Pg2 of the isoquinoline can either remain present (X=Pg2) or be also removed (X=H). A salt of the compound D may also optionally be formed in acidic medium.
For example, in the case where Pg1 represents a tert-butyl carbamate, the amine of the derivative C is released using an acid in an anhydrous medium, such as hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane. The amine carried by the isoquinolinyl group will also be released to give the compound D in which Pg2 becomes a hydrogen atom (X=H). Furthermore, in the case where Pg1 represents a benzyl carbamate, the amine of the derivative C can be selectively released by catalytic hydrogenolysis in ethanol or methanol, in the presence of palladium-on-charcoal, in which case the protective group Pg2 on the amine of the isoquinoline will remain present in the derivative D (X=Pg2).
Particular Embodiment for Step 5a.
The derivative D can subsequently be reacted in an aprotic solvent, such as dichloromethane, THF or DMF, with a sulphonyl halide of formula R3—SO2Hal, where R3 is as defined above in connection with the formula (I) and Hal represent a halogen atom, preferably Cl. The reaction is carried out in the presence of a base, in particular a tertiary amine, such as triethylamine or N,N-diisopropylethylamine, at a temperature of between −10° C. and 50° C., to result in the sulphonamide of structure E.
Particular Embodiment for Optional Step 6a.
Optionally, the sulphonamide E is subsequently deprotected to result in the compound of formula (I) in accordance with the present invention.
During this stage, the removal of the protective group Pg2 and optionally the cleavage of the O—R1 bond (R1 being not H) are carried out using organic chemistry techniques well known to a person skilled in the art.
For example, when R1 is methyl and Pg2 is trityl, the Pg2 group is removed by reaction with trifluoroacetic acid in dichloromethane or else with anhydrous hydrogen chloride in dioxane and then the R1 group can optionally be removed by hydrolysis of the ester using sodium hydroxide in an appropriate solvent or mixture of solvents, such as THF, ethanol and water.
The salt of the compound of formula (I) may be obtained by the addition of the corresponding acid.
Particular Embodiments for Optional Step 7a.
According to a first embodiment, compounds of formula (I) in which R1 represents an alkyl, a cycloalkyl or a cycloalkylalkyl may be obtained by transesterification of a compound of formula (I) as obtained in step 6a with the corresponding R1—OH (alcohol, cycloalkylalcohol or cycloalkylalkylalcohol), in the presence of an alkoxide of metal such as titanium (IV) isopropoxide. This reaction is generally conducted at a temperature comprised between 20° C. and the reflux temperature of the reaction mixture.
According to a second embodiment, compounds of formula (I) in which R1 represents a H atom may be obtained from a compound of formula (I) where R1 is C1-C6 alkyl, cycloalkyl or cycloalkylalkyl as obtained in step 6a by hydrolysis of R1.
More particularly, the hydrolysis may be carried out in aqueous acidic media such as 1M hydrochloric acid at a temperature comprised between 20° C. and the reflux temperature of the reaction mixture, such as 80° C. to provide the corresponding carboxylic acid where R1 is Hydrogen.
According to a third embodiment, compounds of formula (I) in which R1 represents a Rb—O—Ra—, Rd-O—C(O)—O-Rc-, or Rf—C(O)—O—Re— group as defined above may be obtained from a compound of formula (I) where R1 is C1-C6 alkyl, cycloalkyl or cycloalkylalkyl as obtained in step 6a by hydrolysis of R1 in order to obtain the corresponding compound of formula (I) with R1 being H, this hydrolysis being optionally followed by an esterification with the corresponding R1-Hal where Hal is a halogen atom such as Cl.
More particularly, the hydrolysis may be carried out in aqueous acidic media such as 1M hydrochloric acid at a temperature comprised between 20° C. and the reflux temperature of the reaction mixture, such as 80° C. to provide the corresponding carboxylic acid where R1 is Hydrogen. The resulting carboxylic acid is then esterified by reacting the acid with the corresponding compound Rb—O—Ra-Hal, Rd-O—C(O)—O-Rc-Hal, or Rf—C(O)—O—Re-Hal where Hal represents a halogen atom, such as Cl. The compound Rb—O—Ra-Hal may be formed in situ in the presence of Rb—O—Ra—OH with thionyl halogenide, such as thionyl chloride. This esterification reaction may be carried out in the presence of an organic base such as diethylisopropylamine or an inorganic base such as potassium or cesium carbonate at room temperature. Additionally, potassium iodide could be added in the reaction medium for halogen exchange and to improve the alkylation process leading to esters of formula (I) where R1 represents Rb—O—Ra—, Rd-O—C(O)—O-Rc-, or Rf—C(O)—O—Re—, Ra, Rb, Rc, Rd, Re and Rf having the above definitions.
In Scheme 1, the starting compounds and the reactants, when their method of preparation is not described or cited above or below (for instance in the examples), are commercially available or are described in the literature or else can be prepared according to methods which are described therein or which are known to a person skilled in the art.
According to another of its aspects, another subject-matter of the invention is the compounds of formula A, B, C, D and E. These compounds are of use as intermediates in the synthesis of the compounds of formula (I).
where R1 is H or an alkyl, a cycloalkyl or a cycloalkylalkyl-, R2, R2′ and R3 are defined above, Pg, is an amino protective group, X is H or Pg2 and Pg2 is an amino protective group.

Sulphonylaminopyrrolidinone derivatives, their preparation and their therapeutic application


An exercise machine for exercising the muscles of the upper body, in which a pushing or pulling movement can be performed in a direction approximately between horizontal and vertical towards or away from the shoulder joint of the user, with the user seated in the same position.

1. Field of the Invention
The invention relates to exercise machines, in particular those which are used to exercise the muscles of the upper body, being the back, chest and shoulders.
The muscles of the back are used in movements which involve moving the hands towards the body, typically a pulling movement. This can mean a rowing movement, where usually both hands are pulled from being outstretched in front of the body to the chest, or a pull-up movement where the hands grasp a secure point above the head and the body is lifted until the head is level with the point. The chest muscles are used to push the hands away from the body to become outstretched in front of the body, approximately opposite to a rowing movement. The shoulder muscles are used to lift the hands above the head, which is the opposite to a pull-up movement.
2. Related Art
Current machines that allow a rowing movement are of two types in which the user is either seated or sanding. With seated machines, the user either sits on the floor or on a seat, and pulls on a bar attached to the end of a cable that is passed beneath one pulley and over the top of a second pulley attached to a weight. The second pulley is positioned above the first such that, when the cable is pulled, the weight is lifted towards the second pulley, providing resistance to the pulling movement. A further type of machine used in a seated rowing movement uses a pivot with two arms attached to it at approximately 90 degrees to each other. One aim is approximately vertical, with a bar or handle fixed on its end for the user to hold and pull, and the second arm is approximately horizontal with weights attached to its end. When the first arm is pulled on, it rotates about the pivot and rotates the second arm about the pivot, lifting the weight, and providing resistance to the pulling movement.
A machine that is used with the user standing comprises an arm, one end of which is pivotally fixed to the floor with weights placed on the other end. A handle is fixed towards the weighted end of the aim. The user stands astride the arm and grasps the handle and, whilst bent over, lifts the weight towards his chest in a rowing action.
Machines that allow a pull-up movement comprise a cable, one end of which is pulled on by the user, wherein the cable extends vertically above the user to a pulley. The cable is tuned around this pulley until it is horizontal and then around a further pulley until it is vertical, with its end being attached to a weight. The user pulls down on the cable and the cable turns around the two pulleys and lifts the weight to provide resistance. Pivot type machines are also used for pull-up type vertical movements.
Machines have also been used that allow horizontal and vertical movements to be carried out on the same machine. These usually comprise a combination of the two types of machine that use cables. Here, the cable from the vertical movement is extended and passed around a pulley close to the floor. The user sits on the floor and pulls on the end of this cable.
Machines that are used to exercise the chest with the user in a seated position often use an approximately vertical arm attached to a pivot with a further arm attached to the pivot onto the end of which weights are placed. A handle is placed on the end of the first arm and the user pushes on the handle, which rotates both arms about the pivot and lifts the weight. The pivot can be above the head of the user or close to the floor. The resistance can also be provided by a system of pulleys lifting a weight stack. With this type of machine, the exercise movement is along a circular arc about the pivot. Some machines also use a track which runs parallel to the direction of movement of the exercise giving a linear movement.
The shoulder muscles are also exercised on similar machines with pivots or parallel tracks. When the shoulder muscles are exercised in a seated position, the pivot is usually positioned at a point just above the shoulder joint of the user with the arm, which the user holds approximately horizontal.
The limitations of current machines for exercising the back muscles are that, when vertical and horizontal movements are combined on the same machine, saving the number of machines and the amount of weight required, then additional pulleys increase friction on the movement and reduce the effectiveness of the movement, particularly when the weight is lowered, because friction helps to lower the force needed to control the lowering of the weight. The machines also use different body positions for the user, for example, sitting on a seat for one movement and on the floor for another, making the machine uncomfortable and inconvenient to use.
Some machines also allow the muscles of the back, chest and shoulders to be exercised on the same machine. These use different methods to exercise each muscle group, for example, the chest is often exercised on a pivoted arm, and the vertical pull downs for the back performed with a cable passing over a pulley and lifting a weight. The position of the body of the user may also be different for exercising different muscles. For example, the user may sit in an upright position to exercise his chest and have to lean forwards to exercise his shoulders with the same equipment.
Another limitation is that only approximately horizontal and vertical type pushing or pulling movements are allowed on current machines, however, the muscles of the back are capable of pulling movements at any angle between horizontal or below, and vertical, and the muscles of the chest and shoulders can push at any angle between horizontal and vertical.


A device for fixing an object to the edge of a flat support, the support having a top face on which the object is to be fixed and a lower face. A vertical section piece, positionable close to the edge of the support, is perpendicular to the plane of the support. The upper end of the section piece has an element which engages and holds the object on the top face of the support, e.g. rods projecting into a cavity in the object. An arm extending perpendicular to the section piece supports at one end thereof a cam for being selectively moved to press against and released from pressing against the lower face of the support. The section piece passes through an opening in the arm and the arm with the cam thereon is tiltable with reference to the section piece for locking the arm along the section piece. A lever then rotates the cam to press against the lower face of the support.

The present invention concerns a device for fixing an object to the edge of a flat support, especially for fixing a tool of a vise or similar type to a workbench.
Tools of the vise type are traditionally either permanently or removably secured to a flat support.
In the former case, the tool is secured by being screwed directly to the workbench, possibly via a turntable that allows the tool to be rotated. This kind of device is more particularly reserved for large tools and fixed set-ups, in a workshop for example. In the latter case, the tool has a clamp at its bottom which is intended to grip the edge of the workbench and a screw is tightened against the lower face of the bench. This kind of device is more particularly reserved for mobile worksites, especially when the workbench is small, and does not permit the vise to remain permanently attached.
This kind of device has a drawback of not allowing the tool to be attached immediately, as it is necessary, after having unscrewed the screw from the clamp, to adjust the openness of the clamp to suit the thickness of the support, then to tighten the screw. This sometimes creates the risk of damaging the lower face of the support.
It is sometimes necessary either to alter the position of the tool on the workbench or to remove the tool and replace it by another tool, suitable for a different kind of work.

Device for fixing an object to the edge of a flat support


Laser ray transmitting colored polyolefin resin composition containing an anthraquinone salt forming dye below; and method of laser welding wherein welding a portion of contact of a laser ray transmitting material of said resin composition and a laser ray absorbing material by irradiating laser ray so that the laser ray transmitting material transmits the laser ray and the laser ray is absorbed in the laser ray absorbing material with the laser ray transmitting material and the laser ray absorbing material in contact with each other:

Laser welding of synthetic resin materials can, for example, be conducted as described below. As shown in FIG. 1, one part incorporating a laser ray transmitting material and another part incorporating a laser ray absorbing material are brought into contact with each other. When irradiating laser ray from the laser ray transmitting material side to the laser ray absorbing material, the laser ray that has transmitted the laser ray transmitting material is absorbed in the laser ray absorbing material and generates heat. By this heat, the laser ray absorbing material is molten around the portion that has absorbed the laser ray, and the laser ray transmitting material is also molten, the resins of the two parts fuse together, and upon cooling sufficient welding strength is obtained and the laser ray transmitting material and the laser ray absorbing material are joined firmly. Features of laser welding include the capability of welding without bringing the laser ray generation portion in contact with the portion to be welded, the minimal thermal effect on the surrounding portion because the heating is localized, freedom from the problem of mechanical vibration, the capability of welding of fine portions and structures, high reproducibility, maintenance of high air-tightness, high welding strength, inconspicuous welded portion, and no generation of dust etc.
Traditionally, resin parts have been joined together by clamping with clamping parts (bolts, screws, clips, etc.), adhesion using adhesives, vibration welding, ultrasonic welding, etc. According to laser welding, labor saving, productivity improvements, production cost reductions, etc. can be achieved because secure welding is achieved by simple operation to provide strength equivalent to or more than the levels expected by conventional method and in addition vibration and heat have minimal effects. With these features, laser welding is suitable for the joining of functional components, electronic components, etc., for which the avoidance of the influence of vibration or heat is desired in, for example, automobile industry, electric/electronic industry and other fields, and is applicable to the joining of resin parts of complex shapes.
As a technology concerning laser welding, Japanese Patent Laid-Open No. HEI-11-170371 describes a method of laser welding comprising a process wherein laser ray is irradiated so that it focuses on a portion where an opaque part comprising a laser ray absorbing thermoplastic synthetic resin and a colorless transparent part comprising a laser ray transmitting thermoplastic synthetic resin are in contact with each other. In this case, however, when viewed from the colorless transparent part side, the welded portion differs from the non-welded portion in color and smoothness, posing a problem of poor appearance.
Additionally, WO02/36329 describes laser welding of a polyolefin resin using an anthraquinone dye and a perinone dye as colorants. However, if a common neutral dye is used to color a polyolefin resin, the dye is unlikely to fix due to the weak binding of polyolefin resins to dyes and in addition because the neutral dye used is very highly soluble in resins, posing a problem of the bleeding phenomenon, in which the dye migrates elsewhere in the event of contact with another polyolefin resin. This has been a critical problem not only in the use of laser welding, but also in general situations of coloring polyolefin resins.
The present invention has been developed in view of the aforementioned problems in the prior art, and is intended to provide a laser ray transmitting colored polyolefin resin composition that is highly transmittable for laser ray wavelength band (wavelengths from 800 nm to 1200 nm, e.g., 808, 820, 840, 940, and 1064 nm), that undergoes no color fading of the colored polyolefin resin part in the heat treatment process prior to laser welding of the resin part, that permits laser welding with substantially no sublimation of dye, and that possesses sufficient anti-bleeding quality, and a method of laser welding using the same laser ray transmitting colored polyolefin resin composition.

Laser light transmitting colored polyolefin resin compositions and process for laser welding

Abstract: A, B: —NH— or —O—; R1-R3: hydrogen, amino, hydroxy, halogen; R4-R13: hydrogen, alkyl, nitro, sulfonic group; Kin+: organic ammonium ion; m: 1 or 2; n: 1 or 2; the sulfonic group is —SO3 or SO3M, the number of —SO3 being m, M representing hydrogen or an alkali metal.


A microactuator for precisely aligning an optical fiber with an optical device and an associated method of fabrication thereof. The microactuator includes a carrier positioned on a base for holding the optical fiber. An alignment frame positioned on the carrier remotely from the optical fiber is adapted to engage the base and the carrier. The carrier is movable relative to the base and the alignment frame. At least one actuator has a beam for engaging the alignment frame and a pad affixed to the carrier. The beam and pad move relative to each other when the actuator is actuated. The actuator is positioned on the carrier so that the beam engages and applies a force to the alignment frame in a predetermined direction when the actuator is actuated. This causes the pad to apply an opposite force to the carrier causing the carrier to move in a direction opposite the predetermined direction for controllably positioning the carrier relative to the base and precisely aligning the optical fiber with the optical device.

In general, microactuators permit an optical fiber to be aligned with an electro-optic device, such as a laser diode or even another optical fiber. Such alignment is particularly desirable for maximizing the percentage of light coupled from the light source (i.e., the electro-optic device) to the optical fiber. In turn, this increases the transmission efficiency of the optical signals. However, the relatively small sizes of both the optical fiber waveguide and the light source complicates the alignment of optical fibers. For example, a typical single mode optical fiber has a light transmitting core diameter of approximately 2 to 10 .mu.m and a suitable light source is usually about the same size.
Commonly assigned U.S. Pat. No. 5,602,955, the entire disclosure of which is incorporated herein by reference, describes various methods and apparatus known in the art for aligning an optical fiber as well as the shortcomings associated with those methods and apparatus. For example, one known method includes aligning the fiber and bonding it in place with solder or some other bonding agent. Such bonding typically requires heating the bonding agent while the fiber is being aligned and then allowing the bonding agent to cool. Unfortunately, heating in this manner often causes misalignment of adjacent optical fibers. U.S. Pat. No. 5,602,955 shows a microactuator which controllably positions an optical fiber without the need for heating during alignment thereby preventing misalignment of adjacent optical fibers.
This patent further overcomes conventional alignment and bonding systems and methods which are generally relatively laborious and time-intensive, particularly in instances in which a number of optical fibers must be individually aligned, and require a variety of relatively complex and costly components which significantly increase the fabrication costs to produce such precisely aligned optical devices.
In addition, the microactuator of U.S. Pat. No. 5,602,955 precisely aligns an optical fiber within a hermetically sealed package, such as a standard 14-pin hermetic butterfly package, in which opto-electronic devices are typically disposed.
Although the microactuator of U.S. Pat. No. 5,602,955 provides a significant improvement over the existing art, further improvements are desired for providing a microactuator which is internally referenced so that it returns to an equilibrium, unenergized position without the need for an external alignment support structure, or well, or external counteract springs. In addition, U.S. Pat. No. 5,602,955 discloses a microactuator fabricated with bimorphic actuators. Therefore, it is also desired to fabricate a microactuator which provides for movement in at least two directions without bimorphic actuators to simplify construction.

Microactuator for precisely aligning an optical fiber and an associated fabrication method


In a method and a compensation arrangement for compensating detent torques of identically constructed synchronous motors, a no-load detent torque and a bad detent torque are measured on a reference motor as a function of a rotor position relative to a stator. A differential detent torque for the reference motor is determined by subtracting the measured no-load detent torque from each measured bad detent torque, and an operating-point-dependent spectral component of the differential detent torque is determined, A model function modeling the spectral component as a function of the operating point is then formed, and a first compensation current, which generates a compensation torque that compensates a detent torque at the instantaneous operating point with a value of the model function, is superimposed for each of the identically constructed synchronous motors on a setpoint current when operating at an instantaneous operating point in a predetermined first operating range.

The present invention relates to a method and a compensation arrangement for compensating detent torques of synchronous motors.
The following discussion of related art is provided to assist the reader in understanding the advantages of the invention, and is not to be construed as an admission that this related art is prior art to this invention.
A synchronous motor usually has detent torques, which interfere with the smooth running of the motor and, like interference variables, affect the regulation of operating parameters of the motor such as a rotational speed or position of the rotor or a rotating motor or a velocity or position of the rotor of a linear motor. The detent torques of synchronous motors normally depend upon manufacturing tolerances, for example manufacturing tolerances which influence the formation of the air gap between the rotors and stators of the motors. Owing to manufacturing tolerances of this kind, the detent torques of identically constructed synchronous motors generally differ from one another. As a general rule, the detent torques are furthermore load-dependent and increase, for example, along with an increasing load torque of a motor. This manufacturing and load-dependency of the detent torques complicates the compensation of the detent torques during operation of synchronous motors.
It would therefore be desirable and advantageous to obviate prior art shortcomings and to provide an improved method and an improved compensation arrangement for compensating detent torques of synchronous motors.

Compensation of detent torques of synchronous motors


Mobile device operation using grip intensity. An embodiment of a mobile device includes a touch sensor to detect contact or proximity by a user of the mobile device; a memory to store indicators of grip intensity in relation to the touch sensor; and a processor to evaluate contact to the touch sensor. The processor is to compare a contact with the touch sensor to the indicators of grip shape and firmness to determine grip intensity, and the mobile device is to receive an input for a function of the mobile device based at least in part on determined grip intensity for the mobile device.

Mobile devices, including cellular phones, smart phones, mobile Internet devices (MIDs), handheld computers, personal digital assistants (PDAs), and other similar devices, may include one more touch sensors for operation to allow entry of inputs to the mobile device.
Such a mobile device will commonly be grasped in a hand for operation. In many circumstances, the holding of the device will be followed by an input into one or more applications or services, or reading information from the screen of the mobile device.
A mobile device may be of a size and shape to allow grasping around the device. However, such a grasp limits the types of input that may be made into the application because the hand that is holding the mobile device is limited by the need to grip and stabilize the mobile device during operation.


The invention relates to industrial safety goggles provided with permanent ophthalmic micas having a full impact protection mica positioned thereon, wherein said impact protection mica is made from polycarbonate, provides protection against ultraviolet rays and can be removed, thereby enabling the frames to be used as ophthalmic glasses. Said goggles include a ventilation area and the ophthalmic micas have an improved visual field owing to the design of the frame to which they are mounted and fixed using angular incisions in the frame. The frame is provided with an open space at both eyes between the mica and the end of the rim, which provides ventilation and prevents the fogging of the graduated micas. The sidepieces of the goggles are designed to curve at the ends thereof, so that the goggles can be put in place without the user having to remove his/her industrial safety helmet. In addition, said sidepieces are provided with removable pad which are press-fitted and which are joined by a cord that enables the goggles to be hung around the neck when not in use. Said cord takes the form of a resistance cord that can break should the goggles be impeded by any object that could cause an accident.

In the field of industrial safety and personal protection equipments, several products have been developed that fulfill basically the purpose of protecting the user against the several classes of risks occurring in the industries and activities endangering the corporal integrity of the user.
Thus, with regard to eye protection, there are equipments such as industrial safety goggles consisting, generally speaking, of an assembly including a protection lens and a support frame, with a rim portion defining a window to receive the protection lens. The main function of said goggles is to protect against dust or elements that can impact against the eyes when a given work is performed.
On the other hand, in the state of the art, there exist devices used to place a removable cover top protect against sun beams on the conventional frame of prescription or graduated lenses, such as illustrated in documents U.S. Pat. No. 5,321,443 and U.S. Pat. No. 4,952,043. With the above device a person requiring graduated lenses can perform his/her activities and also count on the presence of an eye protection element.
Moreover, there exist inserts with a front frame including graduated lenses but without sidepieces, in such a way that the insert can be placed on a special frame permitting the placement of a protection cover for the graduated lenses and thus for the user's eyes, both against sun beams as well as against small objects that could impact against said cover.
Specifically, an attempt to combine ophthalmic or prescription lenses with an impact protection in the goggles without inserts is shown in document WO2005/092262, in which goggles including a first region comprising a primary sight area located in the front part of the goggles and a second region comprising a peripheral sight area surrounding the primary sight area, including optical correction lenses.

Industrial safety goggles with frame for ophthalmic micas and impact protection mica


A firearm lock and a firearm locking method including a key-operated lock, which is lockingly engageable with an interior portion of a firing chamber of a firearm. The lock comprises: a cylinder lock body including a plug rotatable therewithin; an inner multiply grooved generally circular cylindrical portion fixed to or integrally formed with a first end of the lock body; and an outer circular cylindrical portion correspondingly multiply grooved generally circular cylindrical portion, fixed to or integrally formed with the plug for rotation therewith between a locked orientation, wherein grooves on the inner cylindrical portion are arranged out of phase with corresponding grooves on the outer cylindrical portion, and an unlocked orientation, wherein the grooves on the inner and outer cylindrical portions are mutually aligned.

Various types of firearm locks are known in the patent literature. The following U.S. Patents are believed to represent the current state of the art: U.S. Pat. Nos. 5,992,076; 5,488,794; 5,465,519; 5,450,685; 5,419,069; 5,410,832; 5,361,526; 5,357,704; 5,331,759; 5,241,769; 5,239,767; 5,231,236; 5,115,589; 5,062,233; 5,044,105; 4,965,952; 4,835,894; 4,761,906; 4,709,496; 4,672,762; 4,654,992; 4,619,062; 4,532,729; 4,576,021; 4,528,765; 4,461,108; 4,398,366; 4,276,707; 4,266,356; 3,774,333; 3,605,311; 3,504,818; 3,378,943; 3,137,957; 3,089,272; 2,997,802; 2,763,081; 2,327,334; 1,728,902; 1,572,122.
Published PCT Patent Applications: WO 92/15835; 92/13249; 92/10714; 92/06345; 88/09475; 88/06264; 86/00396; and 82/02941.
UK Published Patent Applications: 2,238,604; 2,234,047; 2,215,822; and 2,220,253.
German Offenlegungsschriften DE 4119617; DE 3323501; DE 2920679; and DE 2908066.
German Patent 602163; European Published Patent Application 0163912, and applicant/assignee's PCT Patent Application PCT/US96/03446.
Applicant/assignee's PCT Patent Applications PCT/US96/03446 and PCT/IL98/00228, the disclosures of which are incorporated herein by reference.

Apparatus and method for locking a firearm to prevent unauthorized use thereof


An apparatus for preparing foams exhibiting a uniformly small cell size, a minimum number of ruptured cell walls and a smooth surface from foamable curable compositions comprises means to transport the ingredients of a foamable, curable composition to the input of a static mixer in which the ingredients of the composition are blended to homogeneity prior to being extruded into an exit zone and through an exit orifice. The length to diameter ratio of the mixing zone and the diameter of the exit orifice are within specified ranges.

1. Field of the Invention
This invention relates to a mixing and dispensing apparatus for foamable compositions. More particularly, this invention relates to an apparatus and a method for blending and dispensing the ingredients of foamable, curable organosiloxane compositions. The cured foam is soft, flexible and exhibits a uniform distribution of small diameter cells. The present apparatus and method are particularly useful for preparing small diameter elongated articles such as foamed-in-place gaskets.
2. Background Information
Foamable organosiloxane compositions that generate hydrogen gas as a blowing agent during curing of the composition are known in the art, and are described in U.S. Pat. Nos. 3,923,705; 4,599,367; 4,888,217; and 5,079,292.
The prior art also describes numerous devices for blending two-part compositions containing a thermosetting organic or organosilicone polymer with a compressed gas or a chemical blowing agent in a confined area and dispensing the resultant mixture into the atmosphere where the entrapped gas forms a foam as the composition cures. Devices of this type are described in U.S. Pat. Nos. 4,778,331, which issued to Cobbs et al. and 5,082,142, which issued to Saidman et al. on Jan. 21, 1992. The Saidman et al. patent teaches dissolving the blowing agent in the one of the two parts of the composition and blending the two parts in a static mixer immediately prior to dispensing the composition from the apparatus.
The Saidman et al. patent does not require a particular nozzle configuration at the output of the static mixer to produce a useful foam.
An article by C. Rauwendaal entitled "A Guide To Static Mixers" (Plastics World, May 1992, pages 63-66) defines static mixers as devices designed to "split and reorient the flow and, thus, impart improved distributive mixing to the fluid". This article recommends mixers with a length to diameter ratio of at least 10 to achieve adequate mixing and product uniformity using the most efficient static mixers described in the article. This mixers are identified as type SMX manufactured by Sulzer and type ISG manufactured by Ross.
Rauwendaal considers static mixers containing the Kenics type of mixing element simple and easy to clean, but less efficient. Mixers containing these elements require a length to diameter ratio of at least 29 to achieve efficient mixing.
The present inventor discovered that when a static mixer is used, the diameter of the orifice through which the composition passes when exiting the device is critical to preparing a foam exhibiting uniform cells that are preferably no larger than two millimeters and contain a low percentage, typically less than 10 percent, of cells with ruptured walls. The present method and associated apparatus are based on this discovery. In accordance with the present invention, nozzles with an exit orifice smaller than 1.50 mm permit use of a static mixer containing Kenics type elements with a lower length to diameter ratio (11) than taught by the art, including the aforementioned article by C. Rauwendaal, which recommends a length to diameter ratio of at least 29 to achieve product uniformity using this type of mixing element.

Apparatus for blending and dispensing foamable, curable organosiloxane compositions


In a device for ejecting droplets of an electrically conductive fluid, a vapor suppressing device is provided to suppress vapor of the electrically conductive fluid. The vapor suppressing device includes an electrode, adapted to provide a direct voltage. Further, a method for suppressing vapor of an electrically conductive fluid in a device for ejecting droplets of an electrically conductive fluid is provided.

A printing device for ejecting droplets of an electrically conductive fluid such as a molten metal is known. Such a device may be used for ejecting droplets of a fluid having a high temperature, such as a molten metal or a molten semiconductor.
An example of such a device is described in WO 2010/063576 A1. The device according to WO 2010/063576 A1 comprises a fluid chamber, adapted to contain the electrically conductive fluid and may be used for direct printing of molten metals. In WO 2010/063576 A1, it is described that droplets of the molten electrically conductive fluid are expelled through an orifice of the printing device by generating a Lorentz force in the electrically conductive fluid. Direct printing of molten electrically conductive fluids, such as molten metals may be employed for printing electronic circuits, for example.
However, often, electrically conductive fluids, such as molten metals, release a significant amount of vapor, even at temperatures slightly above the melting temperature. These vapors may be harmful. For example, these vapors may have a strong negative effect on the human health, in case these vapors are inhaled. Second, vapors that precipitate outside of a reservoir or outside of the print head may cause damage to equipment and cause pollution of the system. For example, precipitation of the electrically conductive fluid may hamper the process. The printing process takes place at elevated temperatures. Therefore, the electrically conductive fluid has to be heated. Often, this is done by inductive heating, wherein a induction heating coil is placed around a reservoir comprising the electrically conductive fluid. In case the vapor of the electrically conductive fluid precipitates between the induction heating coil and the reservoir, heating may be hindered and the printing process may be hampered. Moreover, evaporation of the electrically conductive fluid leads to loss of material. This is unwanted, especially if the electrically conductive fluid is an expensive material. Therefore, it is desirable to prevent the vapors of the electrically conductive fluid from escaping from the electrically conductive fluid material reservoir, such as a fluid chamber, into the environment.
It is an object of the invention to mitigate the above problems.

Device for ejecting droplets of an electrically conductive fluid, vapor suppressing means for use in said device and a method for suppressing vapor of an electrically conductive fluid


Copyrighted electronic media are packaged in a secure electronic format, and registered on associated registration server, which serves to provide on-line licensing and copyright management for that media. Users are connected to the server, e.g., through a computer network or the Internet, to enable data transfers and to transact licenses to utilize the media. Packaged electronic media are typically created by an author or derivative user of the work. Once the packaged media is registered on the server, the media is made available for limited use and possible license through an authorization server. This limited use is specified within the minimum permissions data set assigned to each packaged media. Without a license, users are typically permitted to view the packaged media—through a system which unpackages the media—but cannot save or otherwise transfer the media without obtaining auxiliary permissions to do so from the authorization server. The electronic media is authenticated through digital signatures and optional encryption.

Copyright infringement and theft has increased enormously in the computer age, particularly with respect to information data transfers through the Internet. Further, electronic email and the communication and connectivity of local and wide area networks (LANs and WANs, respectively) have facilitated unauthorized use of copyrighted materials by permitting tagging and/or enclosing of almost any electronic media, such as application software, authored text files and graphics, and musical sounds.
On-line services such as COMPUSERVE™ and AMERICA ONLINE™ do provide some measure of copyright protection by assessing on-line charges to the access of protected databases and to the download of selected files. However, there is little to prevent that on-line user from retransmitting any downloaded files to another user connected on the Internet. If the user is also connected to a network, those downloaded files are also subject to remote access from yet another unauthorized user.
The problems associated within electronic copyright infringement are well known, particularly by those parties injured by the unauthorized use of copyrighted materials. For example, the unauthorized copying of copyrighted magnetic diskettes, and the electronic email and tagging and/or enclosing of copyrighted files can result in a direct monetary loss to the owner of the copyrighted works, in addition to an unaccounted for gain for the unauthorized user. With the expansion of the Internet and other computerized networks, the aggregate amount of such losses and gains is substantial.
Even the U.S. Commerce Department recognizes that serious copyright problems exist with the burgeoning growth of electronic data transfers between networked computers and particularly through the Internet. Early in September 1995, for example, the Commerce Department issued a white paper entitled "Intellectual Property and the National Information Infrastructure." The paper highlights the need to protect copyrighted information that is resident in cyberspace, where unauthorized users can copy original works of authorship, including movies and books, by pressing a couple of keystrokes. See, V. Sussman, Copyright wrong? A fight brews over who gets to own the future (cyberspace), U.S. News & World Report, Sep. 18, 1995, v119 n11 p99(1).
In the prior art, methods have been developed to enhance copyright protection of electronic media. For example, AT&T Bell Laboratories has developed a system which makes tiny adjustments to the spacing between words so that every copy of a document utilizing the system is "unique." These electronic adjustments are detectable by computers only because they are too small for the human eye to notice. By way of another example, DIGIMARC, a company in Portland, Oreg., recently announced a system that encodes data into an image by carefully adjusting the digital representation of individual pixels. As in the AT&T system, the encoded data is not noticeable to the eye and enables some traceability of unauthorized copyright uses. See, S. Steinberg, editor of Wired Magazine, Los Angeles Times column, p2, part D, Aug. 31 (1995).
However, such systems operate only to detect unauthorized usage of copyrighted works in digital form. They do not manage the access to copyrighted works, nor do they provide any systematic way of controlling the rights to copyrighted electronic media.
More particularly, the tracing of copyright clearances to users of copyrighted electronic media in the prior art is a tedious and often impossible task. Specifically, authors and multimedia developers have had only two practical methods for protecting their copyrights of electronic works: one method is to rely upon copyright laws and international treaties to prohibit unauthorized use of the media; and the other is to encrypt the data, so that access is restricted to those users with a decryption key.
In the first method, media developers typically do nothing; or they attach a textual copyright warning—sometimes called a "watermark"—to the media. This type of "protection" ensures free access to the media, but it works only for those honest users and derivative developers who view the work and decide whether they want to license it. However, users and developers of such media cannot be sure of the authorship or integrity of the media. Authenticity is thus sometimes increased by restricting access to the media, such as through the use of a password. By way of example, a password-protected World Wide Web page provides some measure of authenticity, but also discourages the open and free propagation of the information in the media.
In the second method, media developers can utilize powerful encryption tools, readily available in the public domain, such as those tools based on the RSA public key algorithm (Rivest, Shamir, & Adleman, 1977). However, the use of encryption to protect copyrights only serves to restrict access to the information within the media, like the password described above. Moreover, after the work is decrypted on the recipient's computer, the problems of copyright heritage and permissions for derivative development and use of the media remain.
These two methods favor either the user or the owner of the media. In the first method, for example, there is no electronic protection coupled to the media; and it thus favors the free and fair use of the media at the expense of the owners' rights. On the other hand, the second method of encryption favors the owners' rights, at least to a degree. Neither method affords both fair use and ownership protection; and neither provides for automatic management of media rights, including the controlled access to media in derivative works. Further, these methods do not intervene in managing copyrights, and are beneficial only after the copyright issue becomes a problem.
It is, accordingly, one object of the invention to provide systems and methodologies to manage copyrighted electronic media, thereby solving or reducing the afore-mentioned problems.
Another object of the invention is to provide a method for maintaining an electronic bibliographic record of successive data transfers of protected electronic media.
Still another object of the invention provides systems and methods for packaging and unpackaging electronic media within an electronic container to facilitate the management of copyrighted electronic media.
These and other objects of the invention will be apparent from the description which follows.

System and method for managing copyrighted electronic media


A radio transmitter, comprising: a feedback loop (314) which feedback loop comprises a variable attenuator and a signal analyser, means (300, 302, 304, 306, 308, 310, 312) for transmitting a signal on a predetermined radio channel, means (308) for changing attenuation level and for attenuating the feedback signal, means (316) for defining power levels on the radio channel and on the adjacent channels, means (312) for analysing the power levels to generate first and second results of analysis and for comparing the first and second results of analysis, means (318) for delaying a transmitted signal to derive a reference signal, means (312) for comparing the feedback signal and the reference signal to generate an error vector and means (320) for generating a test alarm.

The linearity requirements for radio transmitters usually require a linearized transmitter because power amplifiers are typically linear only in a limited power range. Power amplifiers are required in radio telecommunication systems to amplify signals before transmitting, because a radio signal attenuates on the radio path. Unfortunately, high-power radio-frequency amplifiers tend to be non-linear devices and therefore in many cases they cause distortion. This distortion is expressed, for example, as Inter-Symbol-Interference or out-off-band power in adjacent frequency bands. Typically in many radio communication systems, there are limitations in specifications for power leakage. Another problem which arises with power amplifiers is that the power adjustment is not accurate enough.
Therefore, it is important to find out the transmitters which do not fulfil the quality requirements by measuring and analysing transmitted signals. A testing method and arrangement suitable for production and in situ testing is especially important.

Radio transmitter testing method, radio transmitter and base station


A first imaging unit is configured to capture an image showing a subject in front. A convex reflector is located behind an imaging plane of an optical system formed by the first imaging unit and is configured to share an optical axis with the first imaging unit and mirror a subject beside the convex reflector, a convex portion of the convex reflector being oriented forward. A second imaging unit is configured to share the optical axis with the first imaging unit and capture an image mirrored by the convex reflector. An image processing unit is configured to adjust a resolution of images captured by the first and the second imaging units, obtain a mirror-reversed image from the image captured by the first imaging unit or the image captured by the second imaging unit, and blend the mirror-reversed image with the other image.

1. Field of the Invention
The present invention relates to an image capturing device and an image presentation system, and, more particularly, to a device for capturing an image at a wide angle and a system of presenting an image captured by using the device.
2. Description of the Related Art
Devices capable of capturing an image showing an all-round view are known in the related art. Some of these devices are designed to capture an image by using a combination of a wide-angle camera and a camera configured to capture an image using a curved reflector (see, for example, patent document 1).
[patent document 1] JP2000-322564
Images captured by the related-art device may sometimes contain a discontinuous boundary. In such an image, what should otherwise appear as one subject in the image looks divided. For example, this could happen when a large subject is captured in an image. Further, the motion of a motion-rich subject captured in moving images, which should otherwise be traced smoothly in the moving images, would appear punctuated and discontinuous. In particular, some images may look as if the direction of motion of the subject changes before and after the punctuation with the result that the subject is difficult to track.
Thus, the related-art devices may require further image processing (e.g., reconstruction of divided images) in order to view a subject as a single image. It is therefore believed that the related-art devices capable of capturing an image at a wide leave room for improvement.

Image capturing device for capturing an image at a wide angle and image presentation system


The cooling of a hot fluid is effected using a heat exchanger (11) adapted to receive the hot fluid and liquid coolant for cooling the hot fluid such that the liquid coolant is vaporized. A turbine (12), having an output shaft (19) connected to a fan (18), is responsive to vaporized coolant which expands in the turbine (12) for driving the fan (18) to move a mass of air, and produce vaporized coolant. A condenser (13) receives the expanded vaporized coolant and is responsive to air blown by the fan (18), for condensing the expanded vaporized coolant thereby cooling the same and producing coolant condensate which is then returned to the heat exchanger (11).

Many industrial processes involve low grade cooling of fluids by rejecting heat from a hot fluid into a sink under conditions where the temperature difference is too small to justify using waste heat converters for producing electricity. Steam condensers for steam turbine power plants, industrial processes involving distillation operations and producing chemicals, are examples in which low grade heat is rejected into ambient air or water. The temperature difference between the fluid to be cooled and the temperature of the heat sink is often so small that recovering heat in the fluid is too costly in terms of the size and expense of a suitable heat exchanger.
In industrial processes of the type described above, air cooling is often utilized sometimes due to a lack of available water, such as sea, lake, or river water, but often to minimize the environmental impact of water cooling. For example, cooling towers are conventionally used in conjunction with water cooled power plant condensers in order to conserve water, and these towers input water from the system into the atmosphere in the form a vapor plume that contributes to air pollution. Furthermore, such installations are noisy and can cause visibility problems particularly the cooling towers are located in the vicinity of roads or highways. Cooling towers further require periodic blow-down to extract undesirable chemicals from the cooling system and, often, the cooling water requires treatment, for example the addition of certain chemicals to the water. Disposal of these chemicals is often an environmental problem.
Frequently, cooling ponds are required which also have their impact on the environment. In addition, cooling towers require large quantities of relatively quality water.
Having selected air cooling, the designer is faced with both cost and operational problems. The cost problems are best appreciated from considering how relatively small temperature differences affect heat transfer. In engineering terms, small temperature differences translates into a requirement for a large heat transfer surface areas. Traditionally, for process cooling, this has resulted in using large numbers of finned tubes through which the hot fluid flows; and this is costly in terms of material and fabrication. Operational problems are concerned with parasitic losses due to the energy required to force large masses of air through the finned tubes, and the energy required to pump the fluid to be cooled at a relatively high velocity through long length, small diameter, finned tubes in order to effect heat transfer. For steam condensation in power plant operations, for example, parasitic losses also arise from the necessity for maintaining a large vacuum in the air-cooled condenser which implies the circulation of relatively large volumes of steam in the condenser. To reduce these parasitic losses, the diameter of the finned tubes can be increased and their length shortened, but this approach increases construction costs and reduces heat transfer efficiency. Furthermore, fans are required which consume electrical power that must be supplied form an external source.
Due to the relatively large heat exchange area and piping needed when air cooling is utilized, indirect air cooling has been used where an additional cooling cycle is introduced. The fluid flowing in the additional cooling cycle cools the hot fluid. Heat is extracted from the additional cooling fluid by passing tile fluid through heat exchangers positioned in a conventional natural draft dry cooling tower. By using water as the cooling fluid in the additional cooling cycle, a direct contact condenser has been used in steam operated power plants. Experience reported in ASME paper 90 JPGC/PWR-25, however, shows that the anticipated advantages concerning the efficiency, compared with a conventional surface condenser, could not be achieved. In addition, the increased quantity of water brought about by the use of the additional cooling cycle caused problems with the main cycle. As disclosed in the ASME paper, the alternative solution was a surface indirect condenser used for condensing steam exiting the condenser. In both of these approaches, substantial additional equipment had to be used including a dry, natural draft, cooling tower.
There are other problems in industrial, or other processes involving air cooling a hot fluid that is "dirty" i.e., contains foreign material that fouls the interiors of the finned tubes. The large number and the long length of these tubes often present formidable cleaning problems. In air-cooled steam condensers, the large number of tubes and the potential for leakage at their header connections represent a further problem.
It is therefore an object of the present invention to provide a new and approved method of and apparatus for cooling hot fluids which substantially overcomes or significantly reduces the problems outlined above.

Method and apparatus for cooling hot fluids


An interface to integrated switch control software includes a front-end interface coupled to a network; a back-end interface coupled to the integrated switch control software; and an interface control component that manages implementing requests from the network with the integrated switch control software. A method of interfacing to integrated switch control software includes coupling a front-end interface to a network; coupling a back-end interface to integrated switch control software; and managing the implementation of requests from the network with the integrated switch control software.

FIG. 1 shows a typical telecommunication system. The central office (CO) (12) provides telecommunication services to subscribers (14) and (16). Each CO in the network (10) provides service to subscribers in a small geographic region. Thus, CO (12) provides services to its local subscribers (14) and (16) and CO (13) provides services to its local subscribers (15) and (17). Each subscriber in the entire network (worldwide) is given a unique identification number, e.g., a telephone number, IP address, etc. The fundamental operation of any CO is to physically connect subscribers to the network (10). This is accomplished via a hardware device known as a switch. Generally speaking, a switch is a network device that directs a signal through a network. Various network platforms and transport architectures are known in the art. Examples include basic circuit switched telephony, voice over "X" (wherein X may be DSL (digital subscriber line), FTTH (fiber-to-the-home), HFC (hybrid fiber coaxial line), IP (internet protocol), frame relay, asynchronous transfer mode, etc.), and wireless switching.
Referring to FIG. 2, a typical CO contains, among other things, a switch (20), a billing module (22), an operation system support module (24), and a customer service module (26). The switch (20) is a hardware component that connects a subscriber to the network or another subscriber. A billing module (22) is used to bill the subscriber for basic service rates, optional features, and usage. Most telephone billing systems contain a rater, which evaluates the applicable billing rates for usage of different carriers at different times of the day in order to choose the most cost effective route, or at least properly bill a subscriber. The operation system support module (24) is often used to keep track of inventory, assets, circuit ID, network designation, and orders. The customer service module (26) is usually used by a customer service representative to maintain subscriber information, change optional services, long distance carriers, reconcile billing errors, etc.
Each of the above systems are typically provided by separate vendors and rely on proprietary internal architectures. Because of this, upon receiving a request for new service or change in service from a subscriber, the changes need to be entered separately into the customer account for the subscriber in the customer service module (26), the subscriber options in the operation system support module (24), and customer profile in the billing module (22), and finally, the switch (20) must be programmed to allow the subscriber to access the new service(s).
In recent years, telecommunication service providers have added many enhanced telephone services such as Caller ID, 3-Way Calling, Call Forwarding, Call Waiting, Last Number Redial, Call Rejection, etc. Telephone service providers also offer other special features for telephone subscribers such as least cost routing, specialized billing, and blocks of telephone numbers. Together with the enhancement of services offered by telecommunication companies and at least in part due to the enhancement of services, switches have been designed to incorporate more robust control software. Likewise, with the ever-growing popularity of the Internet, telecommunication service providers have enhanced and increased availability of data services, e.g., dial-up and full-time connections to the Internet from the home or office.

Interface to integrated switch control software