A compound of formula (I) which is an agonist at the adenosine Al receptor, wherein Y, Z, and W represent heteroatoms, and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof for use in therapy.

The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Publications in this area include WO 98/16539 (Novo Nordisk A/S) which describes adenosine derivatives for the treatment of myocardial and cerebral ischaemia and epilepsy; WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which relates to adenosine derivatives possessing antihypertensive, cardioprotective, anti-ischaemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk A/S) which describes N,9-disubstituted adenine derivatives which are substituted in the 4xe2x80x2 position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders involving cytokines in humans.
Thus the invention provides a compound of formula (I) which is an agonist at the adenosine A1 receptor
wherein
X represents O or CH2;
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 alkylO(CH2)n where n is 0-6, C3-7 cycloalkyl, C1-6 hydroxyalkyl, halogen or a C1-6 straight or branched alkyl, C1-6 alkenyl or C1-6 alkynyl group optionally substituted by one or more halogens.
Y and Z represent O, N, CH, N(C1-6 alkyl)
W represents CH, O, N, S, N(C1-6 alkyl)
and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents hydrogen or a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof for use in therapy.
Preferably the compound is of formula (Ia)
wherein
X represents O or CH2;
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 straight or branched alkyl optionally substituted by one or more halogens, C3-7 cycloalkyl, C1-6 hydroxyalkyl or halogen.
Y and Z represent O, N, CH
W represents CH, O, N, S
and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
The invention further provides pharmaceutical compositions of formula (I) or (Ia) together with a pharmaceutically acceptable diluent or carrier.
It will be appreciated that certain compounds embraced by formula (I) are novel per se. A particular group of compounds may be defined by formula (Ib). Therefore, the invention further provides compounds of formula (Ib) which are agonists at the adenosine A1 receptor
wherein
X represents O or CH2;
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 alkylO(CH2)n where n is 0-6, C3-7 cycloalkyl, C1-6 hydroxyalkyl, halogen or a C1-6 straight or branched alkyl, C1-6 alkenyl or C1-6alkynyl group optionally substituted by one or more halogens.
Y and Z represent O, N, CH, N(C1-6 alkyl)
W represents CH, O, N, S, N(C1-6 alkyl)
and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents hydrogen or a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(CO1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd-(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
with the proviso that when R4 and R5 both represent H, R2 represents halogen, R3 cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH3, C1-3alkoxy
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Preferably, the compound is of formula (Ic):
wherein
X represents O or CH2;
R2 represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1-6 straight or branched alkyl optionally substituted by one or more halogens, C3-7 cycloalkyl, C1-6 hydroxyalkyl or halogen.
Y and Z represent O, N, CH
W represents CH, O, N, S
and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H.
R4 and R5 independently represent H or a C1-6 straight chain or branched alkyl group.
R1 represents a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4)alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), xe2x80x94CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n, where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a C1-6 straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2xe2x80x94(C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)n-CO2Rc, -(alkn)-CONRcRd, -(alk)n-CORc, -(alk)n-SORe, -(alk)n-SO2Re, -(alk)n-SO2NRcRd, -(alk)nORc, -(alk)n-(CO)mxe2x80x94NHSO2Re, -(alk)n-NHCORc, -(alk)n-NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl
with the proviso that when R4 and R5 both represent H, R2 represents halogen, R3 cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH3, C1-3alkoxy
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Conveniently the adenosine A1 agonists of the general formula (I) above exhibit greater activity at the adenosine A1 receptor than the other adenosine receptor subtypes, particularly A3. More particularly the compounds exhibit little or no agonist activity at the the A3 receptor.
It will be appreciated that wherein R1 and/or R2 in compounds of formula (I) contain one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula (I) and mixtures thereof. Otherwise the stereochemical configuration of compounds of the invention is as depicted in formula (I) above.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight or branched chain alkyl group. Examples of suitable alkyl groups within R1 and R2 include methyl, ethyl, n-propyl, l-propyl, n-butyl, s-butyl, t-butyl and 2,2-dimethylpropyl.
As used herein, the term xe2x80x9calkylenexe2x80x9d means a straight or branched chain alkylene group containing 1-6 carbon atoms, e.g. methylene.
As used herein, the term xe2x80x9cC2-6alkenylxe2x80x9d means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable C2-6alkenyl group.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
By aliphatic heterocyclic group defined for R1 is meant a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may optionally be substituted as defined hereinabove.
The term heterocyclic aromatic group defined for R1 refers to an aromatic mono or bicyclic ring system comprising from 5 to 10 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, which ring system may optionally be substituted as defined hereinabove.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. A particularly suitable pharmaceutically acceptable salt of the compounds of formula (I) is the hydrochloride salt. Other acids such as oxalic, while not, in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates may be, for example, hydrates.
Examples of W, Y and Z containing heterocyclic groups include isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles and thiadiazoles.
Preferred W, Y and Z containing heterocyclic groups are isoxazoles, and 1,2,4- and 1,3,4- oxadiazoles.
R2 preferably represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine.
Conveniently, R1 may represent (alk)n-C3-6 cycloalkyl wherein n is 0 or 1 and the said cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, and OH or is unsubstituted. Preferably n is zero. More preferably, the cycloalkyl group is unsubstituted or monosubstituted with OH and more preferably the cycloalkyl ring has 5 carbon members. Most preferably, the cycloalkyl group is hydroxycyclopentyl. p Alternatively R1 may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of xe2x80x94CO2xe2x80x94(C1-4)alkyl.
Conveniently, the aliphatic heterocyclic group is unsubstituted or when the substituent is xe2x80x94CO2(C1-4)alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom.
Preferably the heterocyclic ring is 6 membered and more preferably contains only one O, N or S heteroatom. Most preferably when the heterocyclic ring is unsubstituted the heteroatom is O. Most preferably when the heterocyclic ring is substituted the heteroatom is N.
Alternatively, R1 may represent a straight or branched alkyl of 1-6 carbon atoms optionally with at least one S(xe2x95x90O)n and where S(xe2x95x90O)n is present, optionally substituted with N at a position adjacent to the S(xe2x95x90O)n group; where there is an S(xe2x95x90O)n in the chain, substitution with N at a position adjacent to the S(xe2x95x90O)n group is preferred; where there is an S(xe2x95x90O)n in the chain, preferably n is 1 or 2, more preferably n is 2. The alkyl group conveniently may be unsubstituted or substituted by at least one OH group.
Alternatively R1 may represent a phenyl group which is substituted by one or two substituents selected from OH, alkyl, particularly C1-4 alkyl and halogen. Preferably the phenyl is disubstituted in the 2,4 positions. Preferably both substituents are halogen more particularly, fluorine and chlorine. For example, a particularly preferred combination is 2-fluoro and 4-chloro.
Preferably R4 and R5 represent hydrogen.
It is to be understood that the present invention covers all combinations of particular and preferred groups mentioned above.
Particular novel compounds include compounds of Examples 1-207 herein below.
Preferred compounds include:
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
4-{9-[5S-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester;
(2S,3S,4R,5R)-2-(5-Isopropyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
4-{9-[5S-(5-Cyclopropyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester;
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-fluoro-phenylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(5-Ethyl-oxazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-[6-(2S-hydroxy-cyclopent-(S)-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-5-[6-(2S-hydroxy-cyclopent-(S)-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-tert-Butyl-isoxazol-5-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
ethyl 4-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate;
(2S,3S,4R,5R)-2-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-5-{6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-5-[6-(isobutylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(cyclopropylamino)-9H-purin-9-yl]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol;
2-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)-N-methylethanesulfonamide;
(2R,3R,4S,5S)-2-[6-(3,4-difluoroanilino)-9H-purin-9-yl]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3S,4R,5R)-2-[5-(tert-butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5R)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-{6-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol;
2-[(9-{(2R,3R,4S,5S)-5-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide;
2-[(9-{(2R,3R,4S,5S)-5-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-(3-methylphenyl)ethanesulfonamide; p0 2-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(5-methyl-1,3-oxazol-2-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)-N-methylethanesulfonamide;
(2R,3R,4S,5S)-2-[6-(cyclopentylamino)-9H-purin-9-yl]-5-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(5-ethyl-1,3,4-oxadiazol-2-yl)-5-[6-(isopropylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-{2-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl}-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol formate (1:2);
(2R,3R,4S,5S)-2-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-5-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-tetrahydro-furan-3,4-diol diformate;
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol;
ethyl 4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate;
(2R,3S,4R,5R)-2-[5-(tert-butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3S,4R,5R)-2-(5-isopropyl-4H-1,2,4-triazol-3-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(5-methyl-1,3-oxazol-2-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-methylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-propylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
ethyl 4-({2-chloro-9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate;
(2R,3R,4S,5S)-2-(2-chloro-6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-(2-chloro-6-{[2-(ethylsulfonyl)ethyl]amino}-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol;
ethyl 4-[(9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate;
(2S,3S,4R,5R)-2-[3-(hydroxymethyl)isoxazol-5-yl]-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5S)-2-[6-(2-chloroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol;
(2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[6-(piperidin-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol;
(2R,3R,4S,5R)-2-{2-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl}-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3,4-diol formate;
(2S,3S,4R,5R)-2-(3-bromoisoxazol-5-yl)-5-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(methylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(propylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(isopropylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(ethylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
2-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-2-chloro-9H-purin-6-yl)amino]-N-ethylethanesulfonamide
2-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-2-chloro-9H-purin-6-yl)amino]-N-isopropylethanesulfonamide
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-pyridin-3-ylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(4-hydroxybutyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
2-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide
(2R,3R,4S,5S)-2-[6-(cyclopentylamino)-9H-purin-9-yl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3,4-diol
ethyl 4-[(9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-cyclopropylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-{6-[(1-butyrylpiperidin-4-yl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol
isopropyl 4-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(2,2,2-trifluoroacetyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol
methyl 4-[(9-{(2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-chloroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-(2-chloro-6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9-H-purin-9-yl)-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
2-[(2-chloro-9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]1tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide
ethyl 4-[(2-chloro-9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate
(2R,3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[2-chloro-6-(2-fluoroanilino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[2-methoxy-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
ethyl 4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-2-methoxy-9H-purin-6-yl}amino)piperidine-1-carboxylate
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[2-(ethylsulfonyl)ethyl]amino}-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-2-methoxy-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(2-fluoroanilino)-2-methoxy-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-2-methoxy-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-5-[6-(cyclopropylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol
(2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol.
Compounds according to the invention have applicability as inhibitors of lipolysis i.e. they decrease plasma free fatty acid concentrations. The compounds may thus be used in the treatment of hyperlipidaemias. Furthermore, as a consequence of their anti-lipolytic activity, the compounds have the ability to lower elevated blood glucose, insulin and ketone body levels and therefore may be of value in the therapy of diabetes. Since anti-lipolytic agents have hypolipidaemic and hypofibrinogenaemic activity, the compounds may also show anti-atherosclerotic activity. The anti-lipolytic activity of compounds of the invention has been demonstrated by their ability to lower the concentration of non-esterified fatty acids (NEFA) in starved rats dosed orally according to the method described by P. Strong et al. In Clinical Science (1993), 84, 663-669.
In addition to their anti-lipolytic effect, the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction. The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina.
Furthermore, the compounds of the invention are useful as cardioprotective agents, having applicability in the treatment of ischaemic heart disease. As used wherein the term xe2x80x9cischaemic heart diseasexe2x80x9d includes damage associated with both myocardial ischaemia and reperfusion, for example, associated with coronary artery bypass grafting (CABG), percutaneous translumenal coronary angioplasty (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery including in particular cardiac transplantation. The compounds of the invention additionally are useful for treating ischaemic damage to other organs. The compounds of the invention may also be valuable in the treatment of other disorders arising as a result of widespread atheromatous disease, for example, peripheral vascular disease (PVD) and stroke.
The compounds may also inhibit renin release and thus be of use in the therapy of hypertension and heart failure. The compounds may also be useful as CNS agents (e.g. as hypnotics, sedatives, analgesics and/or anti-convulsants particularly finding use in the treatment of epilepsy).
In addition, the compounds of the invention may find use in the treatment of sleep apnoea.
The compound of formula (I) and pharmaceutically acceptable acid addition salts thereof are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically of a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compound of formula (I) and its pharmaceutically acceptable acid addition salts may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis (RA) and osteoarthritis (OA), neuropathic pain (e.g. post herpetic neuralgia (PHN), trigeminal neuralgia, neuropathies associated with diabetes and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compound of formula (I) may also be used in the treatment or prevention of pain associated with migraine, tension headache and cluster headaches and pain associated with Functional Bowel Disorders (e.g. Irritable Bowel Syndrome), non cardiac chest pain and non ulcer dyspepsia.
Additionally, when topically administered, the compounds of the present invention exhibit analgesic and anti-inflammatory activity and are therefore useful in a number of chronic inflammatory pain conditions such as OA, RA and neuropathic conditions such as fibomyalgia and PHN.
Accordingly, the invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or whereby the therapy involves the treatment of ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering from a CNS disorder, sleep apnoea or pain.
In a further aspect, the invention provides a method of treatment of a human or animal subject suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain, which method comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a human or animal suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ishaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain.
In respect of the above mentioned ischaemic treatment, it has been found that according to a particularly unexpected aspect of the present invention, not only does administration of a compound of formula (I) prior to ischaemia provide protection against myocardial infarction, but protection is also afforded if the compound of formula (I) is administered after the ischaemic event and before reperfusion. This means that the methods of the present invention are applicable not only where ischaemia is planned or expected, for example in cardiac surgery, but also in cases of sudden or unexpected ischaemia, for example in heart attack and unstable angina.
It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.
The pharmaceutical composition comprises, as active ingredient, at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutical carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering from a CNS disorder, sleep apnoea or pain.
There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier and/or excipient.
Compositions according to the invention may be formulated for topical, oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The compositions may be adapted for sustained release.
For topical administration, the pharmaceutical composition may be given in the form of a transdermal patch.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents (e.g. mannitol) as appropriate.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of formula (I) may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
A proposed dose of the compounds of the invention for administration to man (of approximately 70 kg body weight) is 1 mg to 2 g, preferably 1 mg to 100 mg, of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration.
In a yet further aspect the invention also provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease (PVD) or stroke, or which patient is suffering from a CNS disorder, sleep apnoea or pain.
The compounds of formula (I) and physiologically acceptable salts or solvates thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups R1, R2 and R3 are as defined for compounds of formula (I) unless otherwise stated.
According to a first general process A, a compound of formula (I) may be prepared by reacting a compound of formula (II)
wherein L represents a leaving group such as a halogen atom (e.g. chlorine), or a linker group capable of binding to a solid phase polymeric support (e.g. a polystyrene resin) and for example may be xe2x80x94SO2C1-4alkylene and P1 and P2 represent hydrogen, C1-6 straight chain or branched alkyl or a suitable protecting group (e.g. acetyl or a protecting group wherein P1 and P2 together form an alkylidine group) with a compound of formula R1NH2 or a salt thereof under basic conditions. The 4xe2x80x2-heterocycle group substituent may be protected if required, for example, see route Bb and V described hereinbelow.
Compounds of formula (II) may be used to produce compounds of formula (I) directly by reaction with the group R1NH2 either in the absence or presence of a solvent such as an alcohol (e.g. a lower alkanol such as isopropanol, t-butanol or 3-pentanol), an ether (e.g. tetrahydrofuran or dioxan), a substituted amide (e.g. dimethylformamide), a halogenated hydrocarbon (e.g. chloroform), an aromatic hydrocarbon (e.g. toluene), dimethyl sulfoxide (DMSO) or acetonitrile, preferably at an elevated temperature (e.g. up to the reflux temperature of the solvent), in the presence of a suitable acid scavanger, for example, inorganic bases such as sodium, cesium or potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine or pyridine, optionally in the presence of a palladium catalyst (e.g. palladium acetate) and phosphine ligand (e.g. R-(+)-2,2xe2x80x2-bis(diphenylphosphino)-1-1xe2x80x2binaphthyl).
Optionally, where at least one of Y, Z and W is N, alkylation may be carried out on a N atom at Y, Z or W at any appropriate stage in the synthesis, for example, see Route X described hereinbelow.
The above reactions may be preceded or followed where appropriate by in situ removal of the P1 and P2 protecting groups. For example when P1 and P2 represent acetyl, this may be effected with an amine such as ammonia or tert-butylamine in a solvent such as methanol or when P1 and P2 represent an alkylidine by acid hydrolysis, e.g. with trifluoroacetic acid (TFA). Interconversion of P1 and P2 protecting groups may occur at any stage in the preparation of the compounds of formula (II), for example when P1 and P2 represent acetyl, compounds of formula (II) may be prepared from compounds wherein P1 and P2 together represent an alkylidine protecting group by acid catalysed removal of the alkylidine protecting group, e.g. with hydrogen chloride in methanol followed by in situ acylation, for example with acetic anhydride in the presence of a base such as pyridine, in a solvent such as dichloromethane.
Otherwise, interconversion of P1 and P2 protecting groups may occur at any stage during the preparation of compounds of formula (II).
It will be apparent to persons skilled in the art that in the preparation of compounds of formula (II) or (I) the 4xe2x80x2-heterocycle may be formed at any stage. For example, heterocycles may be prepared from carboxylic acid or acetylene starting materials before the addition of the purine ring (see Schemes 1, 1a and 2) or heterocycles may be formed after the addition of the purine ring (see Schemes 3, 4 and 5 and Route W). p Compounds of formula (II) where X=O may be prepared by reacting compounds of formula (III)
wherein P3 represents a suitable protecting group, for example acetyl, or a substituent such as C1-3 alkyl, and P1, P2 and R3 are as defined above, with compounds of formula (IV)
wherein L and R2 are as defined above.
The reaction is conveniently carried out in a suitable solvent, such as acetonitrile in the presence of a silylating agent such as trimethylsilyl trifluoromethane sulfonate and a base such as diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively the compound of formula (IV) may first be silylated with a suitable silylating agent e.g. hexamethyldisilazane followed by reaction of the silylated intermediate with a compound of formula (III) and a suitable Lewis acid, e.g. trimethylsilyl trifluoromethanesulfonate in a suitable solvent such as acetonitrile.
Compounds of formula (IV) are either known in the art or may be prepared from known compounds using methods analogous to those used to prepare the known compounds of formula (IV).
As described above, the compounds of formula (III) may be prepared from alternative protected compounds by replacement of the alternate P1 and P2 protecting groups with other P1 and P2 groups. These represent an exchanging of one protecting group for another and will be apparent to those skilled in the art. Compounds of formula (III) may be made for example by the following syntheses:
Compounds of formula (III) may be prepared, for example when the heterocycle defined by W, Y and Z hereinabove represents an isoxazole (optionally substituted) by the following reaction schemes.
General conditions for Stages 1-4 will be known to persons skilled in the art. It will also be appreciated that the reagents and conditions set out in Scheme 1 are example conditions and alternative reagents and conditions for achieving the same chemical transformation may be known to persons skilled in the art. P4 and P5 together represent alkylidine protecting group(s). P6 represents C1-4 alkyl. R3 is as previously defined.
Although scheme 1 shows the preparation of compounds of formula (III) where the heterocycle moiety is an isoxazole it would be apparent to a person skilled in the art that other standard methods could be employed to produce compounds of formula (III) with other heterocycles from carboxylic acid starting materials, such a compound of formula (IIIa), for example, see route Q as described hereinbelow.
An alternative method for synthesis of compounds of formula (III) is shown in Scheme 1a.
General conditions for Stages 1-5 in Scheme 1a will be known to persons skilled in the art. R3, P4, P5 and P6 are as previously defined.
Scheme 2 represents a method of preparing compounds of formula (III) when Y=N, Z=NH, W=CH and R3=H or tautomers thereof. P1, P2 and P6 are as previously defined.
A further process (B) comprises converting a compound of formula (I) into a different compound of formula (I) by modifying the R1, R2 and/or R3 groups therein.
All compounds of formulae (III) are novel intermediates and form a further aspect of the present invention.
Compounds of the formula R1NH2 are either known compounds or may be prepared from known compounds using conventional procedures.
Specific optical isomers of a compound of formula (I) may be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or where appropriate by separation of a mixture of isomers of a compound of formula (I) by conventional means e.g by fractional crystallisation or chromatography.
According to a third process (C), compounds of formula (I) may be prepared from compounds of formula (V) or (VI):
where R1, R2,X, L, P1 and P2 represent groups as previously defined.
Also compounds of formula (VI) may be prepared from compounds of formula (V) by analogous methods to those described in process (A) above.
Synthesis of the compounds of formulae (I) from the corresponding acids of formulae (V) and (VI) will be apparent to a skilled person using conventional synthetic techniques.
As an example, when W=O, Y=N and Z=N in formula 1 above thus defining a 1,3,4 oxadiazole, the synthesis is according to reaction scheme 3. J represents a leaving group L as previously defined, or a NHR1 group. R2, X, P1 and P2 are as previously defined.
Compounds of formula (I) where Z=O, Y=N and W=N (thus defining a 1,2,4-oxadiazole) may be prepared from compounds of formula (V) or (VI) by a first process involving activation of the carboxyl group on the compound of formula (V) or (VI) followed by reaction with an amidoxime of formula HOxe2x80x94Nxe2x95x90C(R3)NH2 in a solvent such as tetrahydrofuran or chloroform, in the presence of a base such as pyridine or di-isopropylethylamine, followed by cyclisation at a temperature of 20xc2x0 C.-150xc2x0 C. in a solvent such as toluene, tetrahydrofuran (THF) or chloroform (see scheme 4). Methods of carboxyl activation include reaction with an acid chloride, such as pivaloyl chloride, or an acid anhydride in the presence of a base such as a tertiary amine, for example di-isopropylethylamine, or with thionyl chloride in dimethylformamide (DMF). Activating agents used in peptide chemistry such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, may also be used. Hydroxyl protecting groups may be removed under conditions known to those practising in the art. For example, the acetonide group may be removed by treatment with an acid (at a temperature of 0xc2x0 C.-150xc2x0 C.) such as trifluoroacetic acid suitably at 0-20xc2x0 C. or acetic acid suitably at 50-150xc2x0 C.
In scheme 4 R2, R3, X, J, P1 and P2 and are as defined above.
Alternatively, a compound of formula (II) may be prepared from a compound of formula (VII), for example, see route U as described hereinbelow. It would be apparent to persons skilled in the art that analagous methods to route U could be used to prepare compounds of formula (I) with other 4xe2x80x2-heterocycles, for example, see route M as described hereinbelow.
According to an general process D, a compound of formula (I) may be prepared from a compound of formula (V), as shown in Scheme 5, followed by removal of the P1 and P2 protecting groups as described previously in process A. It will be apparent to persons skilled in the art that analagous methods to that shown in Scheme 5 could be used to prepare compounds of formula (I) with other 4xe2x80x2-heterocycles using alternative heterocycle syntheses. In Scheme 5, R1, R3, J, P1 and P2 are as previously defined.


A tractor heating system for heating the cabin of a tractor wherein the tractor is carrying a refrigerated trailer. The heating system includes a feed duct in communication with a refer cooling system and the heater of the tractor for communicating heated fluid from the refer cooling system to the heater for heating the tractor cabin. A return duct returns fluid from the tractor heater to the refer cooling system wherein heated fluid from the refer cooling system may be utilized by the tractor heating for heating the cabin of the tractor and also the tractor engine.

Generally, this invention relates to a system for providing heat to a tractor's cabin and engine. In particular, this invention relates to a temperature control system for tractors pulling temperature controlled trailers wherein the cooling system of the temperature controlled trailer is interconnected to the tractor cabin's heating system and the tractor engine's cooling system. Consequently, when the truck occupant is resting, during what is normally idle time for the truck, the tractor's engine can be shut down and the trailer's engine, which is required to continue operating keeping the temperature controlled trailer cool, can be used to provide heat to the tractor's cabin and engine.
Normally, during cold climate, a tractor's engine is kept continuously running at idle when the tractor is parked to provide electrical power and heat to the tractor's cabin when the occupant is sleeping. This process, however, is not economical or environmentally safe. Such practice reduces the life of the engine, requires more frequent oil changes, wastes fuel, and produces noxious exhaust fumes.
Additionally, many tractor trailers pull temperature controlled trailer units commonly known as refer trailers which carry perishable goods. The refer motors are also required to continuously operate to control the temperature in the refer trailer and prevent perishable goods from spoiling. Thus, when the tractor is parked, two engines are in operation at the same time, for controlling the temperature of two separate compartments, the refer trailer and the tractor's cabin.
U.S. Pat. No. 4,825,663 discloses an auxiliary power system that provides heating to a tractor's engine and to a tractor's cabin when the tractor's engine is not running. In addition, the auxiliary engine provides electrical power to the main engine's electrical system. This auxiliary system, however, requires redundant equipment and an additional engine separate from the tractor's engine resulting in the the overall weight of the tractor and trailer to increase. However, because the overall tractor's weight is an element to the cost of operation, the added weight to the trailer is not desirable since the added weight increases the cost of operation of the trailer.
U.S. Pat. No. 4,756,359 discloses an auxiliary system for providing air conditioning and heating for the tractor's cabin, as well as heat for the tractor's engine. This auxiliary system, however, uses a belt system to connect the auxiliary system with the main engine's air conditioning compressor and alternator. The hot exhaust from the auxiliary engine provides the heat to the tractor's cabin and engine via heat exchangers. The additional auxiliary engine in this system also adds to the overall weight of the tractor and consequently is not desirable.
Accordingly, it is an object of the present invention to provide heat to a tractor's cabin in an economical manner when the tractor is parked;
Furthermore, it is an object of the present invention to provide heat to a tractor's cabin when the tractor is parked by utilizing the heat from a refrigerated trailer's engine; PA1 Also, it is an object of the present invention to provide heat to a tractor's cabin by interconnecting the refrigerated motor's coolant system to the cabin heating system; PA1 Furthermore, it is the object of this invention to provide heat to both the tractor's cabin and the tractor's engine while the tractor's engine is shutdown to avoid cold startups which increases the difficulty in starting;

Tractor trailer temperature control for tractors with refrigerated trailers


A data-signal-recovery circuit includes a flip-flop and a controller. The flip-flop has an adjustable sampling threshold, and, in response to a sampling clock, is operable to generate a recovered digital signal having a first level if an input data signal is above the threshold and having a second level if the input data signal is below the threshold. The controller is operable to adjust the threshold and phase shift of the sampling clock. Because the flip-flop has an adjustable sampling threshold, one can calibrate the flip-flop to the characteristics of the eye pattern at the flip-flop's input node.

In today's high-frequency digital communication systems, a receiver typically recovers from the received data signal a "clean" data signal, from which processing circuitry can accurately recover the data carried by the signal. Many communication media such as metal wires (e.g., twisted pair), coaxial cables, PC board traces, or the atmosphere (i.e., wireless communications) are "lossy," particularly at high frequencies. That is, these communication media degrade the signals that they carry, particularly the high-frequency components of these signals. A digital signal typically has relatively sharp transition edges, and thus typically includes signal components having relatively high frequencies. Consequently, in addition to attenuating a digital signal, a lossy communication medium may corrupt the phase of and/or smoothen the signal's transition edges, and one or more of these degradations may cause the processing circuitry to recover erroneous data from the signal. Therefore, in addition to amplifying the received digital signal, a high-frequency-digital-signal receiver typically re-sharpens the transition edges and reduces or removes the phase jitter from these edges to allow the processing circuitry to more accurately recover the data.
FIG. 1A is a block diagram of a conventional high-frequency digital communication system 10, and FIG. 1B is a diagram of a high-frequency digital signal 12 at three points (12a, 12b, 12c) within the system.
Referring to FIG. 1A, the system 10 includes a transmitter 14 for generating the digital signal 12a (FIG. 1B) on an output terminal 15, a lossy transmission medium 16 for carrying the transmitted digital signal, and a receiver 18 for receiving the degraded digital signal from the medium 16, for recovering a logic signal and the data carried by the logic signal, and for processing the recovered data. For example, the transmitter and receiver 14 and 18 may be two computers networked via the medium 16, which may be a PC board trace, fiber-optic or copper cable. The receiver 18 includes an input terminal 20 for receiving the degraded digital signal from the medium 16, and includes a sampler 22 for recovering a clean digital signal from the degraded digital signal. The sampler 22 includes a D flip-flop 24 having input and output nodes 26 and 28 and a clock node 30, and includes a circuit 32, which recovers a sample clock from the degraded data signal and provides the sample clock to the D flip-flop. The receiver 18 may also include pre-sampler circuitry 34, such as a preamplifier, input equalizer, or demodulator.
Referring to FIGS. 1A and 1B, the operation of the communication system 10 and the recovery of the clean digital signal by the sampler 22 is discussed. At the output terminal 15 of the transmitter 14, the data signal 12a has an amplitude A and relatively sharp transition edges 36. But the communication medium 16 degrades the signal such that at the input terminal 20 of the receiver 18, the amplitude of the degraded signal 12b is significantly lower than A, and the transition times of the edges 26 are reduced. Furthermore, the degraded signal 12b may include phase jitter that is not apparent in FIG. 1B. Fortunately, the sampler 22 generates a recovered digital signal 12c by effectively recovering from the degraded signal 12b the amplitude—the pre-sampler circuitry 34 may also assist with amplitude recovery, and the recovered amplitude may be other than A—the sharp edges 36, and the phase stability of the signal 12a. Specifically, the D flip-flop 24 has a trigger, i.e., detection, threshold. In response to each sampling edge—here the rising edge—of the sample clock, the flip-flop 24 generates on its output node 28 the recovered digital signal 12c having a logic 1 level if the amplitude of the degraded signal 12b at the flip-flop's input node 26 is higher than the detection threshold, and generates the recovered digital signal having a logic 0 level if the amplitude of the degraded signal is lower than the detection threshold. Consequently, the processing circuitry (not shown in FIG. 1A) can more accurately recover the data from the recovered signal 12c than it can from the degraded signal 12b.
To optimize the accuracy with which the sampler 22 generates the recovered digital signal 12c, one may determine the characteristics of the degraded data signal 12b at the input terminal 20 of the receiver 18, and calibrate the sampler to these characteristics.
Referring to FIGS. 2A and 2B, one may characterize a data signal by the size and shape of its "eye."
FIG. 2A is an eye pattern 40 of the data signal 12a of FIG. 1B at the output terminal 15 of the transmitter 14. The eye pattern 40 is the superposition of these data sequences back on itself over time, at its bit period The region 42 bounded by the rising/falling edges 36 is the eye opening of the pattern 40.
Similarly, FIG. 2B is an eye pattern 44 of the degraded data signal 12b of FIG. 1B at the input terminal 20 of the receiver 18. The region 46 bounded by the smoothened rising/falling edges is the eye opening of the pattern 44.
Referring to FIGS. 2A and 2B, one can see that the degradation (i.e., attenuation, transition-edge smoothening, and phase jitter) that the medium 16 imparts to the data signal 12a causes the eye 46 of the degraded data signal 12b to be significantly smaller both in voltage and in time than the eye 42 of the signal 12a. The thicker boundary of the eye pattern 44 is caused by amplitude and phase jitter. That is, the amplitude and phase jitter experienced by the degraded signal 12b causes multiple eye patterns to overlay one another at slightly different amplitudes and phases, thus making the signal-trace lines to appear thicker than those in FIG. 2A (the signal 12a experiences significantly less amplitude and phase jitter). Consequently, the thicknesses of the eye-pattern boundary are a rough measure of the ranges of the amplitude and phase jitter experienced by the degraded signal 12b.
Still referring to FIGS. 2A and 2B, in mathematical terms, the eye pattern 44 represents the randomized distribution of the phase (time, i.e., the horizontal "X" dimension) and amplitude (amplitude, i.e., the vertical "Y" dimension) of the signal caused by noise and other degradation of the signal. More specifically, the eye opening 46 is bounded by randomized traces; and could be characterized as contours of varying probabilities. So one can characterize the pattern 44 in terms of probability of the trace lines passing to one side or another of a particular point when the signal represents a particular logic level. As an example, the point 47 away from the optimal center, is analyzed. When the signal represents a logic 1, at the rising edge of the sample clock (which is aligned to the point 47 in the X or time dimension), the probability that the trace line, and thus the signal amplitude, is greater than the detection threshold (which is aligned to the point 47 in the Y or voltage dimension) may be greater than 99%. Similarly, assuming a symmetrical system, when the signal represents a logic 1, at the rising edge of the sample clock the probability that the signal amplitude is less than the detection threshold is less than 1%. This indicates that less than 1% of the time, the sampling circuitry (not shown in FIGS. 2A and 2B) will erroneously characterize the sampled data. If this error rate is too high, then one can attempt to find another sampling point that provides a lower error rate. As discussed below, one typically attempts to determine the "optimum" sampling point that provides the lowest error rate. The optimum sampling point is often, but is not always, near the center point 48 of the eye 46. In this example, the bit-error-rate (BER) is effectively 1 in 100, or BER=10=2. In a typical communication system, the acceptable BER is well below 10−9.
Referring to FIGS. 1A and 2B, to generate the recovered digital signal 12c having the lowest error rate possible, one calibrates the sampler 22 to best match the characteristics of the eye pattern 44 of the degraded data signal 12b. Typically, one performs this calibration by adjusting the phase of the sample clock and the detection threshold of the D flip-flop 24 such that the sampling point 47, which is the intersection of the sampling edge—here the rising edge—of the sample clock and the sampling threshold, is as close as possible to the optimum sampling point, which in this example is the center of the eye 46. For illustration, consider the sampling point 47, which is not at the center of the eye 46. Because of relatively large (beyond that indicated by the eye-pattern traces in FIG. 2A) amplitude and phase jitter intermittently experienced by the degraded signal 12b the signal maybe above or below the threshold at point 47, thus giving rise to a possible errors in the recovered digital signal 12c. For example, if signal 12b is logically low, and jitter causes this signal to be temporarily located at a position above the sampling threshold of point 47, then the sampler 22 will erroneously generates the recovered digital signal 12c having a logic 1 level. Consequently, the farther the sampling point 47 is from the optimum sampling point 48 (here the center of the eye), the higher the chance of error in, and thus the higher the error rate of the recovered digital signal 12c. Conversely, the closer the sampling point 47 to the optimum sampling point 48 of the eye 46, the lower the chance of error in, and thus the lower the error rate of, the recovered data signal 12c. Furthermore, changes in the operating parameters (e.g., temperature) of the sampler 22 may shift the sampling point 47 farther from the optimum sampling point 48 of the eye 46. Therefore, to maximize the safety margin and thus to minimize errors in the recovered data signal 12c, one typically desires the sampling point 47 to be as close as possible to the optimum sampling point 48, which in this example is the center of the eye 46.
Unfortunately, measuring the eye 46 at the input terminal 20 of the receiver 18 and manually calibrating the sampler 22 in response thereto is wrought with many problems. For example, the eye 46 may be different than the eye (not shown) at the input node 26 of the D flip-flop 24, particularly where the receiver 18 includes the pre-sampler circuitry 34. Therefore, aligning the sampling point 47 with the center of the eye 46 at the input terminal 20 is no guarantee that the point 47 is also aligned with the center of the eye at the input node 26, and, thus, such alignment may not provide an acceptable error rate for the recovered digital signal 12c. Furthermore, the characteristics (e.g., shape, probability distribution) of the eye 46, the detect threshold of the flip-flop 24, and the phase of the sample clock may drift over time, thus requiring periodic manual recalibration of the sampling point 47. Or, noticeable drift may occur during operation of the receiver 18, and may thus increase the error rate of the recovered digital signal 12c. In a severe situation, the error rate may increase so much as to cause the receiver 18 to fail.
Still referring to FIGS. 1A and 2B, some manufacturers have proposed including in the receiver 18 circuitry (not shown) for measuring the eye of the degraded signal 12b at a node inside the receiver, and calibrating the sampler 22 according to this internal eye.
But this proposed solution has several limitations. For one, although this proposed circuitry within the receiver 18 measures the eye at a node that is electrically closer to the flip-flop input node 26 than the input terminal 20 is, this internal eye may still be different than the eye at the node 26. Furthermore, the proposed circuitry is single-ended, and thus cannot be incorporated in differential receivers. In addition, the proposed circuitry samples each degraded data signal to determine the boundary of the data eye. In many circumstances, this rate of sampling may be unnecessary, and thus a waste of power.

Data-signal-recovery circuit, data-signal-characterizing circuit, and related integrated circuits, systems, and methods

Avago Technologies General IP (Singapore) Pte. Ltd.


The invention relates to a procedure for the preparation of D-(-)-lactic acid in which a strain of Lactobacillus bulgaricus capable of converting lactose into D-(-)-lactic acid to an extent of more than 50%, is cultivated in a medium containing lactose. It is known that galactose-positive Lactobacillus strains produce mainly L-lactic acid, and galactose-negative strains produce D-(-)-lactic acid almost exclusively, but leave the galactose part of lactose unchanged, the D-(-)-lactic acid being thereafter recovered. Strains suitable for use in the present procedure are Lactobacillus bulgaricus CBS 743.84, CBS 687.85, and CBS 688.85.

Such a process is known from the European Patent Application No. 0,072,010. In said known process use is made of the L. bulgaricus strain DSM 2129 which appears to be capable of producing D-(-)-lactic acid in high yield in a relatively short time from lactose or glucose. It appears from the description, however, that the strain is not capable of producing acid from galactose, which means that only the glucose part of the lactose is used for the production of the lactic acid and the galactose part remains unchanged.
Hitherto, no strains of Lactobacillus species were known which are galactose-positive and produce D-(-)-lactic acid almost exclusively. It is true that it is reported in Bergey's Manual of Determinative Bacteriology (8th edition) that L. bulgaricus is galactose-positive and produces D-(-)-lactic acid almost exclusively, but later investigation revealed that the type strain ATCC 11842 cannot convert any galactose into acid [J. Gen. Microbiol. 74, 289-297 (1973)]. Furthermore, it appears from Appl. Environm. Microbiol. 45, 1932-1934 (1983) that strains of L. helveticus and L. bulgaricus which are galactose-positive always produce a mixture of D- and L-lactic acid in which the L-isomer predominates, and that strains of L. lactis and L. bulgaricus which are galactose-negative always produce D-(-)-lactic acid almost exclusively.

Procedure for the preparation of D-(-)-lactic acid with Lactobacillus bulgaricus

Cooperatieve Weiproduktenfabriek "Borculo" W.A.


An agricultural sprayer includes a centrifugal pump used for transferring fluid from a nurse tank to fill the sprayer tank. It is sometimes required that the centrifugal pump be primed in order to perform the transfer of fluid and this priming is done by creating a vacuum in a priming line that is connected to a suction line extending between an inlet of the pump and to a discharge line of the nurse tank, with the vacuum being caused by routing a flow of compressed air through a venturi having its throat coupled to the priming line.

It is a common practice during agricultural spraying operations to reload the sprayer tank from a tank carried by a nurse vehicle. Oftentimes the nurse tank liquid level is lower that the sprayer pump inlet, especially when the sprayer pump is used with a high clearance sprayer vehicle where the pump is mounted high on the vehicle chassis. A centrifugal pump is a cost effective method of transferring fluid quickly, but such pumps are not able to prime themselves when the liquid source is lower than the pump inlet. Therefore, it is common in the industry to mount centrifugal transfer pumps on the nurse vehicle in a location lower than the liquid level of the nurse vehicle tank.
However, locating a centrifugal transfer pump on the nurse vehicle has some disadvantages in cost, automation and versatility. Specifically, more than one nurse vehicle is often required to service one sprayer. This requires having a transfer pump on each of several nurse vehicles.
While many sprayer manufacturers use centrifugal pumps because they are cost effective and easy to service, and have in the past provided systems which permitted these pumps to serve also as transfer pumps, the aforementioned problem requiring the pumps to be primed when used as transfer pumps has not been adequately resolved, with the result that unprimed pumps may be run dry for a period of time that causes pump failure. Although positive displacement pumps can be used instead of centrifugal pumps since they can be primed from a liquid level lower than the pump inlet, these pumps have the drawbacks of being high in cost and of requiring more time to transfer the fluid.
The problem to be solved then is that of providing a sprayer vehicle with a centrifugal spray pump that can also be used as a transfer pump but which can be easily and reliably primed in the event that the nurse tank fluid level is below the inlet of the pump.


In a scalable video codec, an adaptive Wiener filter with offset aims to minimize the differences between two input pictures or picture regions, and the filter coefficients need to be transmitted to decoder site.

This relates generally to scalable video codecs. The scalable video codec may be bit-depth scalable video codec, spatial scalable video codec, temporal scalable video codec, color space scalable video codec, color format scalable video codec, and etc.
Scalable video codecs enable different picture quality levels to be delivered to different customers, depending on what type of service they prefer. Lower quality video services may be less expensive than higher quality video services.
In a bit-depth scalable video coder, a lower bit depth may be called a baseline layer and a higher bit depth may be called an enhancement layer. The greater the bit depth, the better the quality of the video. In a spatial scalable video coder, a lower picture resolution may be called a baseline layer and a higher picture resolution may be called an enhancement layer. The larger the picture resolution, the better the quality of the video. Other scalabilities include spatial scalability, temporal scalability, signal-to-noise ratio (SNR) scalability, color format scalability, color gamut or color space scalability.
In a scalable video codec, an encoder and decoder may be provided as one unit. In some cases, only an encoder may be provided and, in other cases, only a decoder may be provided. The scalable video coder enables the system to operate with at least the baseline layer. Thus, in low cost systems, only the baseline layer may be utilized and, in higher cost, more advanced systems, one or more enhancement layers may be utilized.
It is advantageous to derive the enhancement layer from the baseline layer. To this end, inverse tone mapping may be utilized in bit-depth scalable video coding to increase the bit depth of the baseline layer to the bit depth of the enhancement layer. In some cases, for example, the baseline layer may be 8 bits per pixel and the enhancement may be 10, 12, or higher bits per pixel.

Adaptive filtering for scalable video coding


It is an object of the present invention to provide a method for efficiently producing a B cell population comprising B cells that recognize a specific antigen. According to the present invention, provided is a method for producing a B cell population, comprising: a step (c) of culturing a cell population comprising B cells together with a specific antigen in the absence of IL-21, in the absence of IL-4, and in the presence of a cytokine other than IL-21 and IL-4, while giving stimulation mediated by CD40 and a BAFF receptor to the cells; and a step (d) of culturing the cell population comprising B cells, while giving stimulation mediated by has to the cells, so as to obtain a B cell population comprising B cells that recognize the specific antigen.

It is anticipated that a monoclonal antibody exhibiting high selectivity to a specific antigen will be developed as an antibody drug, and in particular, the development of antibody drugs targeting cancer cells has progressed. In order to apply a medicament comprising a monoclonal antibody as an active ingredient to the treatment for humans, administration of a human antibody comprising a small amount of foreign antigen is most ideal from the viewpoint of the avoidance of rejection. Hence, a large number of chimeric antibodies and humanized antibodies have been developed.
In general, chimeric antibodies or humanized antibodies used for the treatment of humans are produced by immunizing mice or other animals with antigens several times, then fusing cells of the spleen or lymph nodes with myeloma cells to form hybridomas, and then applying a recombination technique to mouse IgG antibodies produced from the hybridomas. However, it takes much time to use an individual animal such as a mouse or to select hybridomas that generate antibodies exhibiting a high affinity. Moreover, it is necessary to confirm the activity of an antibody obtained by a recombination technique. Thus, it takes time to produce an antibody of interest by the aforementioned method, and further, the effects of the produced antibody cannot be secured until it is administered to a human. Furthermore, when an immunogen exhibits individual toxicity, immunization to an individual is difficult. Further, when a protein antigen that is highly preserved among animal species is used as an antigen, an antibody is hardly generated due to immunological tolerance.
B cells are immune cells that are derived from bone marrow, have B cell receptors (BCR) on the surface thereof, and produce antibodies. Such B cells are generated from hematopoietic stem cells, and the cells are differentiated into B cells through the stage of pro-B cells and pre-B cells. It has been known that the B cells which produce antibodies exhibiting a high affinity for antigens are selected in a germinal center. However, this selection mechanism has not yet been elucidated. If such B cells which produce antibodies exhibiting a high affinity for specific antigens were allowed to artificially proliferate and could be then concentrated, monoclonal antibodies exhibiting a high affinity for specific antigens could be produced in a shorter time than previous techniques.
Patent Document 1 discloses a method for producing an antigen-specific B cell population comprising IgG-positive B cells specific to specific antigens, wherein the method comprises culturing IgG-positive B cells together with the specific antigens in the presence of IL-21, while giving stimulation mediated by CD40, a BAFF receptor and Fas to the cells, and then selecting antigen-specific B cells specific to the specific antigens from the cultured cells, so as to obtain an antigen-specific B cell population comprising IgG-positive B cells specific to the specific antigens.
Patent Document 2 discloses a method for producing a B cell population, comprising a step of culturing B cells in which the expression of a Bach2 gene is increased, in the presence of a means for acting on CD40 and/or a BAFF receptor.

Method for producing B cell population and method for producing monoclonal antibody using same


An aircraft includes a forward fuselage segment, an aft fuselage segment, a wing structure supported from the aft fuselage segment, a tail structure supported from either the aft fuselage segment or the wing structure, and an engine supported from either the aft fuselage segment or the wing structure. A payload module is disposed between and connects the forward fuselage segment and the aft fuselage segment, so as to form the structural attachment between the forward fuselage segment and the aft fuselage segment. The payload module is disconnectable from the forward fuselage segment and the aft fuselage segment such that the forward fuselage segment and the aft fuselage segment are not connected to each other when the payload module is disconnected from the forward fuselage segment and the aft fuselage segment.

This invention relates to the configuration and structure of an aircraft, and, more particularly, to an aircraft having a removable payload module that forms the structural link between a forward fuselage segment and an aft fuselage segment.
An aircraft structure includes a fuselage, a wing, a tail, and one or more engines mounted to the aircraft. A payload such as passengers or cargo is typically carried within the interior of the fuselage. In some cases, the payload may be mounted at least in part exteriorly to the fuselage or affixed externally to the wing.
Some aircraft are optimized for a single type of purpose or mission, such as carrying only passengers, carrying only cargo, or various specific military missions. In other cases, the aircraft is made so as to be convertible between various purposes in order to maximize the potential utilization of the aircraft. In one example, a "cargo conversion" aircraft is built so that the interior of the fuselage may be arranged with rows of passenger seats for some applications. The rows of seats are removable so that containers of cargo may be placed into the interior of the fuselage for other applications. In another example, used with aircraft such as bombers having an internal bay, various packages may be placed into the internal bay. In yet another example, interchangeable external pods may be attached to the airframe.
While operable in specific types of applications, these approaches to convertibility have limitations. If the various payloads are so complex that extensive modifications to the aircraft structure are required in order to effect the conversion, the switching between payloads becomes prohibitively costly and time consuming. For example, some payloads may require access to the exterior of the aircraft, as for instrumentation ports, while other payloads may require that a portion of the payload reside exteriorly to the aircraft. These widely varying types of payloads require that the aircraft undergo extensive modifications, such as adding instrumentation ports or external support pylons to accomplish the conversion. To reduce the cost and time required to make the conversion, the instrumentation ports or external support pylons may be provided as permanent parts of the aircraft structure, but any addition of permanent structure that is used only part of the time reduces the flight efficiency of the aircraft. Such a reduction in efficiency may be acceptable in some situations, but it is not acceptable for aircraft which are expected to perform challenging missions such as long loiter times at high altitudes, for several different types of payloads.
There is a need for an improved aircraft configuration which is both highly flexible as to the types of specialized payloads that it can carry, and is also highly efficient in operation. The present invention fulfills this need, and further provides related advantages.

Aircraft with removable structural payload module


The present invention is a winch clutch assembly, where the deceleration mechanism of the winch contains an additional second internal gear ring, and its outer annular wall is provided with multiple equally distanced fitting indents. The clutch assembly, external to the deceleration mechanism, has clutch levers shifted in longitudinal motion, where the clutch levers are used either to immobilize in the fitting indents of the second internal gear ring of the deceleration mechanism or to release from their immobilized state, enabling the power to transmit or pause to the steel rope sheave of the winch, to accomplish the clutch function.

1. Field of the Invention
The present invention relates to winch clutch assemblies, more particularly, to a deceleration mechanism of the winch which contains an additional second internal gear ring, where its outer annular wall is provided with multiple equally distanced fitting indents, and the clutch assembly, external to the deceleration mechanism, has clutch levers shifted in longitudinal motion, where the clutch levers are used either to immobilize in the fitting indents of the second internal gear ring of the deceleration mechanism or to release from their immobilized state, enabling the power to transmit or pause to the steel rope sheave of the winch, to accomplish the clutch function.
2. Description of the Prior Art
A winch is a lifting appliance capable of winding the sling in or out for the purposes of the lift-up or lay-down of the weight, also named as lifting winch. The spots for installing the winch are such as a high rise for lifting goods vertically in an ascending or descending manner, a jeep or a cross-country vehicle for towing away another vehicle for escaping from danger or for the emergency use by the rescuers. The winch makes use of winding the steel rope in or out to heave the weight or load, so that the power of the winch is designed to operate in driving the steel rope sheave into rotation or reverse rotation, and further to control the release or collection of the steel rope (named power letting off or piling up rope). Since the winch is designed for the collection or release of the steel rope by power, it is limited by the gradual transmission of power internally, which means the speed of collection or release keeps a moderate speed; therefore, for the emergency use (for instance rescuing someone in danger), the release of the rope by power frequently fails to meet the expectation, which indeed worries the rescuers very much. In order to improve the aforesaid drawback, the prior art winches are provided with clutch assembly. Once the clutch is put on "separate" state, the power, transmitted to the steel rope sheave, is being paused, which frees the winding of the steel rope sheave from being restricted by the power, for the release of the rope promptly by labor (named manually releasing the steel rope), and for one more step earlier in seizing the sufferers to be rescued or the objects to be lifted; then followed by returning to "joined" state, resuming the power to the steel rope sheave to achieve the lifting of the weight or the load. Prior art winch clutch assemblies are made up of quite many complex components, which bring about some drawbacks: complicating the procedure for the assembly, putting off the production, and raising the cost; there is a vague difference between the separate state and the joined state for their actions, which quite annoys the operator. By realizing the aforesaid defects, the inventor conceived the ideal of innovation and improvement, which gives birth to the present invention.


An access circuit and method for accessing a single memory having a plurality of access request sources, in which a minimum access time of the memory is adopted as a unit time, a time corresponding to a minimum possible waiting time of each of the plurality of access request sources is adopted as one period, and the period is set as a set of the unit times. The one period is equally divided into divided times in accordance with the number of the access request sources, and each divided time is equally allocated to a corresponding one of the access request sources as an access time therefor. The memory is accessed by the access request sources at every access time allocated to the access request sources. Also provided is a printer apparatus which includes a writing circuit for writing color component data, which represents an image of a plurality of colors, in a single memory in compressed form, a reading circuit for reading color component data of different colors out of respective ones of different addresses of the single memory independently and at predetermined time units, a plurality of decoding circuits for decoding the color component data of each color read out by the reading circuit into corresponding color image data, and an image forming unit for reproducing a corresponding color image based on the image data of each color from the plurality of decoding circuits.

When it is possible to generate a plurality of access requests for accessing a single memory, the conventional practice is to accomplish this by multiple accessing upon assigning a fixed order of priority to the sources that generate the individual access requests.
One disadvantage with the prior art is that a source generating an access request having a high order of priority continously monopolizes the memory, while the access request from a source having a low order of priority is hardly ever accepted. As a result, this source is made to wait an extremely long time for access to the memory.
Conventionally, a memory can be addressed in two ways. One method is to address the memory by means of a two dimensional address map, and the other is to employ a linear address such as an ordinary memory address. In the prior art, a CPU ordinarily is capable of addressing a memory using only one of these accessing methods.
Image data, by way of example, can be processed more efficiently by accessing an image memory using the two-dimensional addressing method. However, if it desired to use a blank space in the image memory as a work area for the CPU, efficiency suffers since the address space of the CPU is a linear address.
Conversely, if a memory address is arranged in the form of a linear address to deal with the CPU address space, the efficiency of memory utilization is improved as seen from the CPU. However, if it is desired to address the memory as e.g. an image memory by means of a matrix, the efficiency of memory utilization declines.
In order to record a full-color image with an apparatus of the kind shown in FIG. 2, four-color data for the four colors Y, M, C and BL (black) is required. Furthermore, since the recording position for each color is different, it is required that the items of color data be supplied to the recording sections for these colors at different timings. Accordingly, an arrangement has been contemplated in which each item of color data is stored in a memory and these items of data are read out of the memory at an arbitrary timing.
However, in order to store the color data representing one sheet of a full-color image, one page of memory capacity is needed for each of the colors Y, M, C and BL, so that the image memory must have a total storage capacity of four pages. This raises a problem in terms of cost. To solve this problem, consideration has been given to an arrangement in which color data is stored upon being compressed in order to reduce the required memory capacity.
If the apparatus shown in FIG. 2 is so arranged that the images of the respective colors are recorded in separate time frames, as by recording the image data for the M color after recording of the image data for the Y color is completed, then the spacing between mutually adjacent recording positions for different colors must at least be made greater than the length of the recording paper. This would result in an apparatus of very large size. Accordingly, it has been contemplated to design an apparatus of compact size by making the spacing between mutually adjacent recording positions for different colors smaller than the length of the recording paper and recording an image on the recording paper at a succeeding recording position before the same recording paper has entirely left the immediately preceding recording position.
However, when it is attempted to reduce the size of the apparatus in this manner, a plurality of image memories corresponding to the various colors are required for storing the four-color image data compressed as mentioned above. These items of color data must be read out simultaneously and decoded, and different color data must be supplied to at least two recording sections simultaneously. Though the four-color image data are indeed compressed, a total of four pages of image memory must be provided, and it is necessary to also provide a plurality of memory control circuits capable of accessing these plural image memories.

Memory access method and circuit in which access timing to a memory is divided into N periods to be accessed from N access request sources


A system and method is described for characterizing glycopeptides which includes a first quadrupole mass filter, a multipole rod set of an ion guide, a lens electrode, an ExD device and a mass analyzer. The multipole rod set is adapted to receive a radial radio frequency (RF) trapping voltage and a radial dipole direct current (DC) voltage The lens electrode is adapted to receive an axial trapping alternating current (AC) voltage and a DC voltage. The ExD device performs electron capture dissociation or electron transfer dissociation, the ExD device being positioned so that an entrance of the ExD device is disposed on the other side of the lens electrode opposite the multipole rod set. The mass analyzer is positioned at an exit of the ExD device for receiving ions from the ExD device.

Glycopeptides are a class of peptide structures that comprise one or more carbohydrate moieties that are covalently bonded to side chains of the amino acid residues that make up the peptide. In several cases, the glycans form a backbone of sugar moieties. Glycopeptides are classified depending on the linkage between the glycan portion (ie, the carbohydrate) and the amino acid residue. In addition, linkage between glycan moieties is also important.
Glycopeptides can be characterized in a limited way using conventional mass spectrometry. Tandem mass spectrometry using collision induced dissociation (CID) can break glycosidic bonds and can be utilized to analyze the glycan portion of the molecule which can include the ordering and identity of the component sugars moieties. In other cases, CID can be used to sequence the peptide region.
Electron based dissociation (referred to generically as ExD herein) which can include electron transfer dissociation (ETD), and various forms of Electron capture dissociation (ECD), such as Hot ECD, can be used for various purposes which can include the sequencing of the peptide portion of the molecule and to identify the site of glycosylation, for example, determination of the site of linkage (e.g., 2, 3, 4 or 6 position) of a monosaccharide. In the latter case, identifying the site of glycosylation can only be performed on glycans that have been released from the peptide, typically by usage of enzyme cleavage. These electron based dissociation methods perform cross-ring cleavage of the sugar rings which allows linkage positions to be determined in subsequent analysis. The identification of linkage position cannot be utilized on glycopeptides themselves (absent the pre-separation of the glycans from the peptides through for example, enzyme cleavage) because electron based dissociation methods performed on intact glycopeptides preferentially disassociate the peptide chains rather the glycan rings.
It is therefore desirous to have techniques and apparatuses that are capable of characterizing glycopeptides in a more thorough manner, which can include identifying the peptide sequence, glycosylated site, glycan components and linkage of each mono-saccharide in a simplified manner.

Apparatus and method for glycopeptide analysis