The invention provides compounds of general formula

The present invention relates to adamantane derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
Adamantane derivatives are known in the art, e.g. from WO 95/04720 for use as gastrin and cholecystokinin receptor ligands, from Chem. Abs. (1977), Volume 86, No. 13 (86: 89560d) for use as analgesics, and from U.S. Pat. No. 3,464,998 as antibiotics.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1xcex2(IL 1xcex2l ) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
It would be desirable to make compounds effective as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X7 receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of general formula
wherein
m represents 1, 2 or 3, preferably 1 or 2;
each R1 independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, preferably a hydrogen atom;
A represents C(O)NH or, preferably, NHC(O);
Ar represents a group
X represents a bond, an oxygen atom or a group CO, (CH2)1-6, CHxe2x95x90, (CH2)1-6O, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CRxe2x80x2(OH), (CH2)1-3O(CH2)1-3, (CH2)1-3O(CH2)2-3O, NR5, (CH2)1-6NR5, NR5(CH2)1-6, (CH2)1-3NR5(CH2)1-3, O(CH2)2-6NR5, O(CH2)2-3NR5(CH2)1-3, (CH2)1-3NR5(CH2)2-3O, NR5(CH2)2-6O, NR5(CH2)2-3O(CH2)1-3, CONR5, NR5CO, S(O)n, S(O)nCH2, CH2S(O)n, SO2NR5 or NR5SO2;
n is 0, 1 or 2;
Rxe2x80x2 represents a hydrogen atom or a C1-C6 alkyl, preferably methyl, group;
one of R2 and R3 represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from (i) C1-C6 alkyl optionally substituted by at least one C3-C6 cycloalkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, and (iv) C3-C8 cycloalkyloxy, each of these groups being optionally substituted by one or more fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen atom;
either R4 represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7, or R4 represents a 3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6N7, the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl;
r is 1, 2, 3, 4, 5 or 6;
R5 represents a hydrogen atom or a C1-C6 alkyl or C3-C8 cycloalkyl group;
R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl, C2-C6 hydroxyalkyl or C3-C8 cycloalkyl group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring; with the provisos that,
(a) when A represents C(O)NH and R4 represents an unsubstituted 3- to 8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and
(b) when A represents C(O)NH and X represents a group (CH2)1-6 or O(CH2)1-6, then R4 does not represent an unsubstituted imidazolyl, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl group, and
(c) when A represents NHC(O) and R4 represents an unsubstituted 3- to 8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and
(d) when A represents NHC(O) and X represents O(CH2)1-6, NH(CH2)1-6 or SCH2, then R4 does not represent an unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl group, and
(e) when A represents NHC(O) and X represents O(CH2)2-3NH(CH2)2, then R4 does not represent an imidazolyl group;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups/moieties containing up to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. When one of R2 and R3 represents a C1-C6 alkyl/C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, it should be understood that one or both of the alkyl and cycloalkyl moieties may be optionally substituted by fluorine atoms. In relation to R4, a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom may be a monocyclic or bicyclic ring system. Further in relation to R4, a 3- to 8-membered saturated carbocyclic ring system may be a monocyclic or bicyclic ring system. When R6 or R7 represents a C2-C6 hydroxyalkyl in the substituent NR6R7, xe2x80x94(CH2)rNR6R7 or xe2x80x94CONR6R7, it will be appreciated that the hydroxyl group will not be bonded to the same carbon atom as the nitrogen atom. When R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring, the ring obtained is monocyclic.
Preferably X represents a bond, an oxygen atom or a group CO, (CH2)1-6, CHxe2x95x90, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CRxe2x80x2(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n or S(O)nCH2.
One of R2 and R3 represents a halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl, or a group selected from (i) C1-C6 alkyl, preferably C1-C4 alkyl, optionally substituted by at least one (e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (ii) C3-C8 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (iii) C1-C6 alkyloxy, preferably C1-C4 alkyloxy, optionally substituted by at least one (e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and (iv) C3-C8 cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), each of these groups being optionally substituted by one or more (e.g. 1, 2, 3 or 4) fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom.
Preferably, one of R2 and R3 represents a halogen (especially chlorine or bromine) atom or a nitro, amino or C1-C6 alkyl (especially methyl or ethyl) group and the other of R2 and R3 represents a hydrogen atom.
R4 may represent a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, preferably C1-C4 alkyl, C1-C6 hydroxyalkyl, preferably C1-C4 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7.
The 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system in the group R4 may be a monocyclic ring system such as pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), 4-piperiden-3-yl, piperazinyl (e.g. 1-piperazinyl), homopiperazinyl,
or a bicyclic ring system such as
Alternatively, R4 may represent a 3- to 8-membered saturated carbocyclic ring system substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7, the ring system being optionally further substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl, preferably C1-C4 alkyl.
The 3- to 8-membered saturated carbocyclic ring in the group R4 is preferably a monocyclic ring system such as a cyclopentyl or cyclohexyl ring.
Specific examples of groups R4 include:
When X represents a bond or a group CO, (CH2)1-6, O(CH2)2-6, O(CH2)2-3O(CH2)2-3, (CH2)1-3O(CH2)2-3, NR5(CH2)2-6, (CH2)1-3NR5(CH2)2-3, O(CH2)2-3NR5(CH2)2-3, NR5(CH2)2-3O(CH2)2-3, NR5CO, SO2 or NR5SO2, R4 preferably represents a group:
When X represents an oxygen or sulphur atom or a group CHxe2x95x90, (CH2)1-6O, OCH2, O(CH2)2-6O, O(CH2)2-3OCH2, CRxe2x80x2OH, (CH2)1-3OCH2, (CH2)1-3O(CH2)2-3O, NR5, (CH2)1-6NR5, O(CH2)2-6NR5, NR5CH2, (CH2)1-3NR5CH2, O(CH2)2-3NR5CH2, (CH2)1-3NR5(CH2)2-3O, NR5(CH2)2-6O, NR5(CH2)2-3OCH2, CONR5, SO, S(O)nCH2, CH2S(O)n or SO2NR5, R4 preferably represents a group:
R5 represents a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group.
R6 and R7 each independently represent a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), C2-C6 hydroxyalkyl or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered, preferably 3- to 6-membered, saturated heterocyclic ring such as a pyrrolidinyl or piperidinyl ring.
Preferred compounds of the invention include:
2-Nitro-3-piperazin-1-yl-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide,
2-Amino-3-piperazin-1-yl-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
2-Chloro-3-piperazin-1-yl-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-piperazin-1-yl-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-(4-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-5-(3-Amino-1-pyrrolidinyl)-2-chloro-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-piperazin-1-ylmethyl-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]-N-(tricyclo[22.214.171.124 3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-[(4-Amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-[(3-Amino-1-pyrrolidinyl)methyl]-2-chloro-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinyloxy)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(R)-2-Chloro-5-(2-pyrrolidinylmethoxy)-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(S)-2-Chloro-5-(2-pyrrolidinylmethoxy)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(3-piperidinylmethoxy)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
cis-5-[(4-Aminocyclohexyl)oxy]-2-chloro-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Methyl-5-(1-piperazinylmethyl)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(1-piperazinylmethyl)-N-(2-tricyclo[22.214.171.124,7]dec-1-ylethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-5-(3-piperidinyloxy)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
trans-5-[(4-Aminocyclohexyl)oxy]-2-chloro-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide,
cis-(+/xe2x88x92)-5-[(3-Aminocyclopentyl)oxy]-2-chloro-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide,
(S,S)-2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(tricyclo[220.127.116.11,7dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(2-methyl 1-piperazinyl)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-5-(3-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide,
(+/xe2x88x92)-2-Chloro-5-(3-piperidinylamino)-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide,
N-[2-methyl-5-(4-piperidinyloxy)phenyl]-tricyclo[184.108.40.206,7]decane-1-acetamide, hydrochloride salt,
N-[2-chloro-5-(4-piperidinyloxy)phenyl]-tricyclo[188.8.131.52,7]decane-1-acetamide, hydrochloride salt,
2-Chloro-5-[(4-piperidinylamino)methyl]-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[[[4-(Aminomethyl)cyclohexyl]amino]methyl]-2-chloro-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[[(4-Aminocyclohexyl)amino]methyl]-2-chloro-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[(1-Azabicyclo[2.2.2]oct-3-ylamino)methyl]-2-chloro-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide,
N-[4-(3-Aminopyrrolidin-1-yl)-2-methylphenyl]-2-(tricyclo[22.214.171.124,7]dec-1-yl)acetamide, dihydrochloride salt,
N-(2-Methyl-4-piperazin-1-ylphenyl)-2-(tricyclo[18.104.22.168,7]dec-1-yl)acetamide, dihydrochloride salt,
cis-4-(3-Amino-cyclopentyloxy)-2-chloro-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro4-(4-piperidinyloxy)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-4-(pyrrolidin-3-yloxy)-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide,
2-Chloro-4-(piperidin-3-yloxy)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro4-(4-piperazin-1-yl)-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-4-(3-pyrrolidinylamino)-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-4-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(xc2x1)-5-[(3-Amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
trans-2-Chloro-5-[[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]methyl]-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
cis-2-Chloro-5-[(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl]-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinylidenemethyl)-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinylmethyl)-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-hydroxy-piperidin-4-yl)-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Ethyl-5-piperazin-1-ylmethyl-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin-4-ylsulfanyl)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin4-ylsulfinyl)-N-(tricyclo[184.108.40.206.7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-(piperidin4-ylsulfonyl)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin4-ylmethylsulfanyl)-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin4-ylmethanesulfonyl)-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperazine-1-carbonyl)-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-([1,4]diazepane-1-carbonyl)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
4-Chloro-N1-(piperidin4-yl-)-N2-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-isophthalamide, hydrochloride salt,
2-Chloro-5-(hydroxy4-piperidinylmethyl)-N-(tricyclo[184.108.40.206,7dec-1-ylmethyl)-benzamide, hydrochloride salt,
(xc2x1)-2-Chloro-5-(hydroxy-3-piperidinylmethyl)-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Bromo-5-piperazin-1-ylmethyl-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(1-piperazinyl)ethyl]-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-[2-(4-Amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(3-piperidinylamino)ethyl]-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[2-(3-Amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(3-pyrrolidinylamino)ethyl]-N-(tricyclo[22.214.171.124,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[2-[(3R)-3-Aminopyrrolidinyl]ethyl]-2-chloro-N-(tricyclo[18.104.22.168,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-[2-(hydroxymethyl)-1-piperazinyl]ethyl]-N-(tricyclo[188.8.131.52,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(2-tricyclo[184.108.40.206,7]dec-1-ylethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-5-(3-Amino-1-pyrrolidinyl)-2-chloro-N-(2-tricyclo[220.127.116.11,7]dec-1-ylethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinylcarbonyl)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[1-hydroxy-1-(4-piperidinyl)ethyl]-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(1-piperazinyl)ethoxy)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(4-piperidinyl)ethoxy)-N-(tricyclo[22.214.171.124,7dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(4-piperidinyloxy)ethoxy)-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-[2-(1-piperazinyl)ethoxy]ethoxy]-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[(5,6-dihydro-1(4H)-pyrimidinyl)methyl]-N-(tricyclo[220.127.116.11,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[[4-[(2-hydroxyethyl)amnino]-1-piperidinyl]methyl]-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[[4-hydroxy4-[[(1-methylethyl)amino]methyl]-1-piperidinyl]methyl]-N-(tricyclo[126.96.36.199,7dec-1-ylmethyl)-benzamide,
2-Chloro-5-[(1,2,3,6-tetrahydro-3-pyridinyl)methyl]-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(3-piperidinylmethyl)-N-(tricyclo[184.108.40.206,7]dec-1-ylmethyl)-benzamide, acetate salt,
2-bromo-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo[126.96.36.199,7]dec -1-ylmethyl-benzamide, and
2-Chloro-5-[(E)-3-piperidinylidenemethyl]-N-(tricyclo[126.96.36.199,7]dec-1-ylmethyl)-benzamide.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
(i) when X represents a CH2 group, R4 represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7 and R4is linked to X through a nitrogen atom, reacting a compound of general formula
wherein one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group xe2x80x94CH2L1 in which L1 represents a leaving group (e.g. a halogen atom) and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x2xe2x80x94Hxe2x80x83xe2x80x83(III)
xe2x80x83in the presence of a base (e.g. diisopropylethylamine), wherein R4xe2x80x2 represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7 and wherein R6 and R7 are as defined in formula (I); or
(ii) when X represents an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, O(CH2)2-6NR5 or O(CH2)2-3NR5(CH2)1-3, reacting a compound of general formula
wherein one of R12 and R13 represents a hydrogen atom and the other of R12 and R13 represents a hydroxyl group and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Yxe2x80x94OHxe2x80x83xe2x80x83(V)
wherein Y represents a bond or a group (CH2)1-6, O(CH2)2-6, (CH2)1-3O(CH2)2-3, NR5(CH2)2-6 or (CH2)1-3NR5(CH2)2-3 and R4 is as defined in formula (I), in the presence of 1,1-(azodicarbonyl)dipiperidine and tributylphosphine (under conditions of the Mitsunobu reaction: Tetrahedron Lett. (1993), 34, 1639); or
(iii) when X represents a bond, an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3 and A is NHC(O), reacting a compound of general formula
wherein one of R14 and R15 represents a group xe2x80x94Xxe2x80x2xe2x80x94R4 and the other of R14 and R15 represents a hydrogen atom, Xxe2x80x2 represents a bond, an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3, L2 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R4 and R5 are as defined in formula (I), with a compound of general formula
wherein m and R1 are as defined in formula (I), optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole); or
(iv) when X represents a bond, an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3 and A is C(O)NH, reacting a compound of general formula
wherein R2 and R3 are as defined in formula (I) and R14 and R15 are as defined in formula (VI) in (iii) above, with a compound of general formula
wherein m and R1 are as defined in formula (I), in the presence of a base (e.g. diisopropylamine); or
(v) when X represents a bond or a group NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3, reacting a compound of general formula
wherein one of R16 and R17 represents a leaving group, L3, such as a halogen atom and the other of R16 and R17 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Zxe2x80x83xe2x80x83(XI)
wherein Z represents a hydrogen atom or a group NHR5, (CH2)1-6NHR5, O(CH2)2-6NHR5 or a group (CH2)1-3O(CH2)2-3NHR5 and R4 and R5 are as defined in formula (I), optionally in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate); or
(vi) when X represents a group CH2O, reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a bond, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(vii) when X represents a group CH2NR5, reacting a compound of formula (II) as defined in (i) above with a compound of formula (XI) as defined in (v) above wherein Z represents a group NHR5; or
(viii) when X represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O, reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a group (CH2)1-3 or O(CH2)2-3, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(ix) when X represents a group CH2NR5CH2 or CH2NR5(CH2)2-3O reacting a compound of formula (II) as defined in (i) above with a compound of formula (XI) as defined in (v) above wherein Z represents a group CH2NHR5 or O(CH2)2-3NHR5; or
(x) when X represents a group CH2 and R4 represents an unsubstituted 4- to 6-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, reacting a compound of formula (II) as defined in (i) above, with a compound of general formula
wherein s and t independently represent 1 or 2; or
(xi) when X represents a group CO, CONR5, NR5CO, SO2, NR5SO2 or SO2NR5 and A is NHC(O), reacting a compound of general formula
wherein one of R18 and R19 represents a group xe2x80x94Xxe2x80x3xe2x80x94R4 and the other of R18 and R19 represents a hydrogen atom, Xxe2x80x3 represents a group CO, CONR5, NR5CO, SO2, NR5SO2 or SO2NR5, L4 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R4 and R5 are as defined in formula (I), with a compound of formula (VI) as defined in (iii) above, optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole); or
(xii) when X represents a group CO, CONR5, NR5CO, SO2, NR5SO2 or SO2NR5 and A is C(O)NH, reacting a compound of general formula
wherein R2 and R3 are as defined in formula (I) and R18 and R19 are as defined in formula (XII) in (xi) above, with a compound of formula (IX) as defined in (iv) above, in the presence of a base (e.g. diisopropylamine); or
(xiii) when X represents a sulfur atom, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent such as n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94Sxe2x80x94SO2xe2x80x94Tolxe2x80x83xe2x80x83(XV)
wherein Tol represents a tolyl group (4-methylphenyl) and R4 is as defined in formula (I); or
(xiv) when X represents a CHOH or CH2 group, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent (e.g. methyllithium/t-butyllithium or n-butyllithium at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94CHOxe2x80x83xe2x80x83(XVI)
wherein R4 is as defined in formula (I), optionally followed by a reduction reaction, e.g. with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or
(xv) when X represents a bond, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent such as n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x95x90Oxe2x80x83xe2x80x83(XVII)
wherein R4 is as defined in formula (I), optionally followed by a reduction reaction, e.g. with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile;
(xvi) when X represents a group SO, oxidising a corresponding compound of formula (I) in which X represents a sulphur atom (e.g. using, as oxidising agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulphate (commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d)); or
to (xvii) when X represents a group SCH2, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent (e.g. methyllithium and/or t-butyllithium at xe2x88x9270xc2x0 C.) and then with a compound of general formula
wherein R4 is as defined in formula (I); or
(xviii) when X represents a group SOCH2 or SO2CH2, oxidising a corresponding compound of formula (I) in which X represents a group SCH2 (e.g. using, as oxidising agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulphate (commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d)); or
(xix) when X represents a group CHxe2x95x90, reacting a compound of formula (II) as defined in (i) above with trimethyl phophite and then with a compound of formula (XVII) as defined in (xv) above in the presence of a base (e.g. lithium diisopropylamide); or
(xx) when X represents a group (CH2)1-6, reacting a compound of general formula
wherein one of R20 and R21 represents a group CHO or a group (CH2)1-5CHO and the other of R20 and R21 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula (XX), R4xe2x80x94H, wherein R4 is as defined in formula (I), in the presence of a reducing agent (e.g. sodium triacetoxyborohydride, in a suitable solvent such as dichloroethane); or
(xxi) when X represents a group (CH2)1-6NR5, (CH2)1-3NR5(CH2)1-3 or (CH2)1-3NR5(CH2)2-3O, reacting a compound of formula (XIX) as defined in (xx) above, with a compound of general formula (XXI), R4xe2x80x94Zxe2x80x2, wherein Zxe2x80x2 represents a group NHR5, (CH2)1-3NHR5, O(CH2)2-3NHR5 and R4 and R5 are as defined in formula (I), in the presence of a reducing agent (e.g. sodium triacetoxyborohydride, in a suitable solvent such as dichloroethane); or
(xxii) when X represents a group (CH2)1-3O(CH2)1-3 or (CH2)1-3O(CH2)2-3O, reacting a compound of formula (XIX) as defined in (xx) above in which one of R20 and R21 represents a group CHO or a group (CH2)1-2CHO and the other of R20 and R21 represents a hydrogen atom, with a reducing agent (such as sodium borohydride), followed by reaction with a compound of general formula (XXII), R4xe2x80x94E, wherein E represents a group (CH2)1-3L5 or O(CH2)2-3L5, L5 is a leaving group (such as a halogen atom or a sulphonate ester group, e.g. p-toluenesulphonate) and R4 is as defined in formula (I), in the presence of a base (such as sodium hydride); or
(xxiii) when X represents a group (CH2)1-6, reacting a compound of formula (II) as defined in (i) above with trimethylphosphite and then with a compound of formula (XVI) as defined in (xiv) above, a compound of formula (XVII) as defined in (xv) above or a compound of general formula (XVIA), R4(CH2)1-4CHO in which R4 is as defined in formula (I), in the presence of a base (e.g. lithium diisopropylamide), followed by a reduction reaction (for example, with hydrogen and a platinum oxide catalyst); or
(xxiv) when X represents a group (CH2)2-6O, reacting a compound of general formula
wherein one of R22 and R23 represents a group (CH2)2-6L6 and the other of R20 and R21 represents a hydrogen atom, L6 represents a leaving group (e.g. a halogen atom or a sulphonate ester group such as p-toluenesulphonate) and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of formula (V) as defined in (ii) above in which Y represents a bond; or
(xxv) when X represents a group CRxe2x80x2(OH) in which Rxe2x80x2 is a C1-C6 alkyl group, oxidising a corresponding compound of formula (I) in which X represents CH(OH) (e.g. using the oxidant dimethylsulphoxide/oxalyl chloride), followed by reaction with a C1-C6 alkyllithium reagent; or
(xxvi) when X represents a group CH2S, reacting a compound of formula (II) as defined in (i) above with a compound of general formula (XXIV), R4xe2x80x94SH, wherein R4 is as defined in formula (I), in the presence of a base (e.g. sodium hydride); or
(xxvii) when X represents a group CH2SO or CH2SO2, oxidising a corresponding compound of formula (I) in which X represents a group CH2S (e.g. using, as oxidising agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulphate (commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d)); or
(xxviii) when X represents a group CH2 and R4 represents a 3-piperidinyl or 2-piperazinyl group, reacting a compound of formula (II) as defined in (i) above with a reagent formed by combining pyridine or pyrazine with an aluminium hydride reagent (e.g. lithium aluminium hydride), followed by a reduction reaction (e.g. with hydrogen and a platinum catalyst); or
(xxix) when X represents a group CHxe2x95x90 and R4 represents a 3-piperidinyl group, reacting a compound of general formula
wherein one of R24 and R25 represents an aldehyde group xe2x80x94CHO, and the other of R24 and R25 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with 2,3,4,5-tetrahydropyridine (Bull. Chem.Soc.Jpn. 1983, 56, 3199), followed by a reduction reaction (e.g. with sodium borohydride in a protic solvent such as methanol); or
(xxx) when X represents a bond, NR5 or NR5(CH2)1-6 and R4 represents a carbon-linked piperidyl or piperazinyl group, reducing a compound of general formula
wherein one of R26 and R27 represents a pyridyl, pyrazinyl, NR5-pyridyl, NR5-pyrazinyl, NR5(CH2)1-6-pyridyl or NR5(CH2)1-6-pyrazinyl group and the other of R26 and R27 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), with a source of hydrogen and a hydrogenation catalyst (such as platinum oxide); or
(xxxi) when X represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O and A is NHC(O), reacting a compound of general formula
wherein one of R28 and R29 represents a group xe2x80x94Xxe2x80x2xe2x80x3xe2x80x94R4 and the other of R28 and R29 represents a hydrogen atom, Xxe2x80x2xe2x80x3 represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O, is L7 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3 and R4 are as defined in formula (I), with a compound of formula (VII) as defined in (iii) above, optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole); or
(xxxii) when X represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O and A is C(O)NH, reacting a compound of general formula
wherein R2 and R3 are as defined in formula (I) and R28 and R29 are as defined in formula (XXVII) in (xxxi) above, with a compound of formula (IX) as defined in (iv) above, in the presence of a base (e.g. diisopropylamine);
and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), (xxiv), (xxv), (xxvi), (xxvii), (xxviii), (xxix), (xxx), (xxxi) or (xxxii) converting the compound of formula (I) to a further compound of formula (I) and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dioxane, xylene or dimethylformamide, at a temperature, e.g. in the range from 0 to 200xc2x0 C., preferably in the range from 0 to 150xc2x0 C.
Compounds of formula (II) in which A is NHC(O) may be prepared by reacting a compound of general formula
wherein L10 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2 R3, R10 and R11 are as defined in formula (II), with a compound of formula (VII) as defined above, optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole).
Compounds of formula (XXX) in which one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group xe2x80x94CH2L1 and L1 represents a bromine atom can be prepared by reacting a compound of general formula
wherein one of R30 and R31 represents a hydrogen atom and the other of R30 and R31 represents a methyl group and R2 and R3 are as defined in formula (I), with N-bromosuccinimide and catalytic azobisisobutyronitrile or dibenzoylperoxide, optionally followed by chlorination with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride.
Compounds of formula (II) in which A is C(O)NH and L1 represents, for example, a bromine atom may be prepared by reacting a compound of general formula
wherein R2 and R3 are as defined in formula (I) and R30 and R31 are as defined in formula (XXXI) above, with a compound of formula (IX) as defined above, in the presence of a base (e.g. diisopropylethylamine), followed by reaction with N-bromosuccinimide and catalytic azobisisobutyronitrile or dibenzoylperoxide.
Compounds of formula (IV) in which A is NHC(O) may be prepared in an analogous manner to compounds of formula (II) in which A is NHC(O), using instead of the intermediate compound of formula (XXX), an intermediate compound of general formula
wherein L11 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R12 and R13 are as defined in formula (IV).
Compounds of formula (IV) in which A is C(O)NH may be prepared by reacting a compound of general formula
wherein R2, R3, R12 and R13 are as defined in formula (IV), with a compound of formula (IX) as defined above, optionally in the presence of a base (e.g. diisopropylethylamine).
Compounds of formula (VI) can be prepared by reacting a compound of general formula
wherein R32 represents a hydrogen atom or a C1-C6 alkyl group, one of R33 and R34 represents a leaving group, L12, such as a halogen atom (e.g. bromine or iodine) or a trifluoromethanesulfonate group and the other of R33 and R34 represents a hydrogen atom, and R2 and R3 are as defined in formula (VI), with a compound of general formula
xe2x80x83Hxe2x80x94Xxe2x80x2xe2x80x94R4xe2x80x83xe2x80x83(XXXVI)
wherein Xxe2x80x2 and R4 are as defined in formula (VI), in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate) (1996 J. Am. Chem. Soc., 7215-6; 1997 J. Am. Chem. Soc., 3395), followed by a hydrolysis reaction (e.g. with sodium hydroxide) and optionally a chlorination reaction (e.g. with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride).
Compounds of formula (VII) may conveniently be prepared by reacting a compound of formula (VI) in which L2 represents a hydroxyl group with diphenylphosphoryl azide in the presence of a base such as triethylamine.
Compounds of formula (X) in which A is NHC(O) may be prepared in an analogous manner to compounds of formula (II) in which A is NHC(O), using instead of the intermediate compound of formula (XXX), an intermediate compound of general formula
wherein L13 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R16 and R17 are as defined in formula (X).
Compounds of formula (X) in which A is C(O)NH may be prepared in an analogous manner to compounds of formula (IV) in which A is C(O)NH, using instead of the intermediate compound of formula (XXXIV), an intermediate compound of general formula
wherein R2, R3, R16 and R17 are as defined in formula (X).
Compounds of formula (XII) can be prepared as described in Syn. Lett. (1998)379-380.
Compounds of formula (XIII) in which Xxe2x80x3 represents a group CO, CONR5, SO2 or SO2NR5 can be prepared by reacting a compound of general formula
wherein one of R35 and R36 represents a group COL14 or SO2L14 and the other of R25 and R26 represents a hydrogen atom, L14 represents a leaving group (e.g. a halogen atom), R37 represents a hydrogen atom or a C1-C6 alkyl group, and R2 and R3 are as defined in formula (XIII), with a compound of formula (XXXVI) in which Xxe2x80x2 represents a bond or a group NR5, in the presence of a base such as diisopropylethylamine and catalytic dimethylaminopyridine, followed by a hydrolysis reaction (e.g. sodium hydroxide) and, optionally, a chlorination reaction (e.g. with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride).
Compounds of formula (XIII) in which Xxe2x80x3 represents a group represents a group NR5CO or NR5SO2 can be prepared by reacting a compound of general formula
wherein one of R38 and R39 represents a group NHR5 and the other of R38 and R39 represents a hydrogen atom, R37 is as defined for compound (XXXIX), and R2 and R3 are as defined in formula (XIII), with a compound general formula (XLI), R4xe2x80x94J, wherein J represents a group COCl or SO2Cl and R4 is as defined in formula (I), in the presence of a base such as diisopropylethylamine.
Compounds of formula (XIV) may conveniently be prepared by reacting a compound of formula (XIII) in which L4 represents a hydroxyl group with diphenylphosphoryl azide in the presence of a base such as triethylamine.
Compounds of formula (XIX) in which one of R20 and R21 represents a group (CH2)1-5CHO and the other of R20 and R21 represents a hydrogen atom can be prepared by oxidising a compound of general formula
wherein one of R40 and R41 represents a group (CH2)2-6OH and the other of R40 and R41 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), using as the oxidising agent, for example, Dess Martin Periodinane reagent.
Compounds of formula (XLII) in which one of R40 and R41 represents a group (CH2)2OH and the other of R40 and R41 represents a hydrogen atom can be prepared from a compound of general formula (X) as defined above, an organolithium reagent such as methyllithium (at xe2x88x9270xc2x0 C.) followed by n-butyllithium (at xe2x88x9270xc2x0 C.), and then treatment with ethylene oxide.
Compounds of formula (XLII) in which one of R40 and R41 represents a group (CH2)3-6OH and the other of R40 and R41 represents a hydrogen atom can be prepared by reacting a compound of general formula (X) as defined above with a compound of general formula
in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), followed by reduction with, for example, hydrogen and a platinum oxide catalyst.
Compounds of formula (XIX) in which one of R20 and R21 represents a group CHO and the other of R20 and R21 represents a hydrogen atom (which are equivalent to compounds of formula (XXV)) can be prepared from a compound of general formula (X) as defined above, with an organolithium reagent such as methyllithium (at xe2x88x9270xc2x0 C.) followed by n-butyllithium (at xe2x88x9270xc2x0 C.) and then with dimethylformamide.
Compounds of formula (XXIII) in which L6 represents an iodine atom or p-toluenesulphonyloxy group may be prepared by reacting a compound of formula (XLII) as defined above with iodine/triphenylphosphine/imidazole or with a sulphonyl chloride such as p-toluenesulphonyl chloride, in the presence of a base such as diisopropylethylamine.
Compounds of formula (XXVI) in which one of R26 and R27 represents a pyridyl or pyrazinyl group and the other of R26 and R27 represents a hydrogen atom can be prepared from a compound of formula (X) as defined above by reaction with a pyridyl or pyrazinyl boronic acid in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0).
Compounds of formula (XXVI) in which one of R26 and R27 represents a NR5-pyridyl, NR5-pyrazinyl, NR5(CH2)1-6-pyridyl or NR5(CH2)1-6-pyrazinyl group and the other of R26 and R27 represents a hydrogen atom can be prepared from a compound of formula (X) as defined above by reaction with a compound NHR5pyridyl, NHR5pyrazinyl, NHR5(CH2)1-6-pyridyl or NHR5(CH2)1-6-pyrazinyl, in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate).
Compounds of formulae (III), (V), (VII), (IX), (XI), (XV), (XVI), (XVIA), (XVII), (XVII), (XX), (XXI), (XXII), (XXIV), (XXVII), (XXVIII), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII) and (XLIII) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) in which one of R2 and R3 represents a nitro group can be converted to compounds of formula (I) in which one of R2 and R3 represents an amino group by reduction using iron powder and ammonium chloride in ethanol/water under reflux conditions. The latter compounds can in turn be converted into compounds of formula (I) in which one of R2 and R3 represents a halogen atom, e.g. chlorine, by diazotization (e.g. with sodium nitrite) and reaction with copper chloride. Compounds of formula (I) in which R6 or R7 represents a hydrogen atom can be converted to compounds of formula (I) in which R6 or R7 represents a C1-C6 alkyl, C2-C6 hydroxyalkyl, C3-C8 cycloalkyl or a 3- to 8-membered saturated heterocyclic ring by standard chemical procedures.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess pharmacological activity. They are therefore indicated as pharmaceuticals for use in the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn""s disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer""s disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
The invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 0.001 mg/kg to 30 mg/kg.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

Abstract: in which m, A, R1 and Ar have the meanings defined in the specification; a process for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.


In a die casting machine that includes a shot cylinder having a ram for injecting metal into a die cavity, an electrohydraulic system for controlling operation of the shot cylinder includes an actuator coupled to the shot cylinder ram. A valve supplies hydraulic fluid to the actuator cylinder as a function of valve control signals. Microprocessor-based digital control electronics includes memory for storing a desired ram velocity profile as an incremental function of ram position. The control circuitry is responsive to signals from a sensor coupled to the actuator, indicative of position at the ram, for retrieving corresponding velocity signals from memory and supplying control signals to the valve as a function of such profile velocity signals. The control circuitry further includes facility for adjusting impact of the shot cylinder ram at the end of a cavity-filling stroke as a function of ram and actuator position and/or pressure, independently of the velocity/position profile, to reduce separation and flashing at the die cavity, and to reduce impact wear and fatigue on the overall die casting machine. A keyboard and associated operator display provide operator programmability and selection from a plurality of velocity/position profiles. The actuator and cylinder ram may be advanced in a manual mode of operation for adjustment and calibration proposes. A display associated with the keyboard graphically illustrates desired and actual velocity/position profiles during operation, together with a profile of actuator drive pressure verses position.

There are numerous applications in the electrohydraulic control field in which it is desired to control motion at an actuator system and load. In a die casting machine, for example, it is desirable closely to control the profile of motion at the so-called shot cylinder that pushes molten metal into the machine die cavity. Specifically, velocity of the shot cylinder ram must be closely controlled as a function of ram position to obtain optimum machine efficiency and throughput, while maintaining product quality and reducing material waste through die separation and flashing, etc. Wear at the cylinder and die cavity are also reduced, and machine productivity therefore is increased, when both velocity and stroke of the shot cylinder ram can be closely controlled and tailored to die cavity volume and configuration.
It is therefore a general object of the present invention to provide an electrohydraulic actuator system that obtains enhanced and precise control of motion at the actuator and load. Another object of the present invention is to provide a system of the described character that embodies state-of-the-art electronic control capability, and yet is easy and economical to implement both in new system construction and in retrofit of existing systems.
A further and more specific object of the present invention is to provide an electrohydraulic system for controlling velocity at an actuator load, such as the shot cylinder of a die casting machine, as a precise yet programmable function of position. A related object of the invention is to provide a shot cylinder control system for a die casting machine that includes a facility for programming and storing a plurality of operator-selectable velocity versus position control profiles, for adjustment of impact force at the end of the ram stroke for reducing die separation and flashing at the machine, and/or for graphic display of desired and/or actual velocity profile at the hydraulic cylinder and ram. Yet another object of the invention is to provide a shot cylinder control system of the described character that employs PC-compatible or other conventional hardware familiar to the operator, and user-friendly state-of-the-art control programming that is easy to employ and yet features enhanced control precision and versatility.

Electrohydraulic control of a die casting machine


A multi-die chip module (MCM) comprises a first die containing a first test controller and a second die containing a second test controller coupled to the first die via an interconnect. The first test controller is configured to place the first die in either a shift mode or a capture mode. The second controller is configured to place the second die in either the shift mode or the capture mode. After a scan shift operation, scan cells are initialized to predetermined values. During the capture operation one die remains in the shift mode and the other die enters the capture mode so that as test bits are shifted into registers associated with output pads on the die in the shift mode, the other die is in the capture mode and captures signals on input pads associated with that die, enabling scan based at-speed testing of the interconnect.

Typically, chip level input/output (IO) interfaces are tested and characterized separately against interface requirements. When two chips are connected on a PCB, minimal system level testing is done using Boundary Scan testing which targets "stuck-at" faults (e.g., short circuits, open circuits). This typically meets the requirements as these interfaces are already characterized completely.
In a multichip module (MCM), multiple semiconductor dies are packaged onto a unifying substrate. The two dies have an interface between them. In MCM devices, the individual die I/Os are not characterized separately unlike chip-level I/Os. Creating test cases manually, for testing and charactering MCM interfaces can be tedious and error-prone and may even prove impossible, as tests targeting multiple fault types need to be taken into account. If these MCM IOs and interconnects are not tested and characterized completely, it can potentially cause functional failures. Hence simple boundary scan testing, which targets stuck-at faults, may not be sufficient for testing MCM interconnects.
Traditionally, MCM interconnects are tested using boundary scan testing. The two dies in an MCM have separate boundary scan test access ports associated with them. Such boundary scan testing methodology comes with all the inherent limitations of the boundary scan testing. For example, boundary scan was originally designed to test the board interconnects where the individual dies are tested and characterized and only stuck-testing is required to test the interface integrity. The interval between the update of test stimulus and capture of the response spans at least 2.5 test clock cycles. This delay makes boundary scan testing insufficient for screening of various problems such as delay defects, cross-talk, simultaneous switching noise etc. In-addition test vector generation requires boundary scan software/custom scripts.
Some at-speed testing strategies pursued for MCM testing includes functional testing, MCM built-in self test (BIST) and oscillation-based methodologies. In functional testing, test-cases are coded to target the MCM interconnect defects. In the BIST methodology, a pseudo-random pattern generator is used to generate random values on one die, and these values are captured on the other die. The values are later checked to verify the integrity of the interconnects. In the oscillation-based methodology, the traditional boundary scan cells are modified and are arranged to form a ring for creating oscillations by having odd number of cells in the ring. In these testing methodologies, targeting the faults leading to reliability issues is quite difficult. Also there is no straightforward method to isolate the failures in post silicon debug. In-addition, the MCM BIST and oscillation based test methodologies involves additional hardware and the targeted tests for traditional fault models are not possible. Also, none of the existing methods take into account clocking and process variations between the dies.


An improved method of playing the conventional manner of play of baccarat and game table apparatus in which a bettor makes a first wager that either a bank hand or player hand will win, the improvement comprising: the bettor having the option of making a second wager that the bank hand and the player hand will comprise in combination a four-of-a-kind of a specific card value, dealing two cards comprising the bank hand and dealing two cards comprising the player hand according to the conventional manner of play of baccarat, determining whether the combination of the bank hand and the player hand is a four-of-a-kind of the specific card value, paying off the bettor a predetermined amount if the bettor's second wager was a winning wager wherein the combination of the bank hand and the player hand is a four-of-a-kind of the specific card value, dealing an additional card to the player hand and an additional card to the bank hand if required according to the conventional manner of play of baccarat, determining a winning hand and a losing hand according to the conventional manner of play of baccarat, paying off the bettor a predetermined amount if the bettor's first wager was on the winning hand according to the conventional manner of play of baccarat and collecting the amount wagered on the losing hand. The game table apparatus comprising: a game board having a generally semicircular peripheral edge about which a plurality of players are located, the game board having designated thereon a series of bet placing boxes corresponding to each of the players and a plurality of ornamental designs corresponding to each of the players, each of the ornamental designs being located at each of the bet placing boxes.

1. Field of the Invention
The present invention is generally directed to a method of play and apparatus for playing a casino game of chance. In particular, the present invention relates to a baccarat game and table layout for mini-baccarat or baccarat.
Moreover, the present invention will be specifically directed to a method of play that provides for an additional side wager or progressive bet to entice players to make additional wagers to receive a predetermined reward.
Also, the present invention will specifically be directed to a method of play that provides for an additional side wager, such as a progressive bet or a proxy progressive bet to entice players to make additional wagers to receive a predetermined reward facilitated by the application of a keypad to process and record all progressive bets electronically.
Furthermore, in order to stimulate and create more interest to the traditional method of playing baccarat, the present invention will introduce:
(1) A baccarat marker; PA1 (2) A baccarat bet box; PA1 (3) A baccarat table layout; and PA1 (4) A baccarat tie call. PA1 a) the bettor having the option of making a second wager that the bank hand and the player hand will comprise in combination a four-of-a-kind of a specific card value; PA1 b) dealing two cards comprising the bank hand and dealing two cards comprising the player hand according to the conventional manner of play of baccarat; PA1 c) determining whether the combination of the bank hand and the player hand is a four-of-a-kind of the specific card value; PA1 d) paying off the bettor a predetermined amount if the bettor's second wager was a winning wager wherein the combination of the bank hand and the player hand is a four-of-a-kind of the specific card value; PA1 e) dealing an additional card to the player hand and an additional card to the bank hand if required according to the conventional manner of play of baccarat; PA1 f) determining a winning hand and a losing hand according to the conventional manner of play of baccarat; PA1 g) paying off the bettor a predetermined amount if the bettor's first wager was on the winning hand according to the conventional manner of play of baccarat and collecting the amount wagered on the losing hand.
2. Description of the Prior Art
Baccarat is one of the more popular gambling games played in casinos or gaming establishments. As is well known, the game is played on an elongated table having a game board displayed along the upper surface of the table. The game board displays certain wagering areas, and the elongated table allows for the seating of multiple players or bettors (1-16) and the positioning of the multiple dealers (3) necessary for operating the casino game. Bettor locations are typically numbered on the table and each bettor location has an area designated for a wager on the bank hand and an area designated for a wager on the player hand. Baccarat uses a standard deck of 52 playing cards and is usually dealt from a shoe having multiple decks that have been shuffled together prior to the beginning of play.
The object of the game of baccarat is for the bettor to successfully wager on whether the bank's hand or the player's hand is going to win. The bettor receives even money for his wager if he selects the winning hand and loses his wager if he selects the losing hand. Because of the rules of play of baccarat, the bank's hand has a slightly higher chance of winning than does the player's hand. Therefore, if the bettor wagers on the bank's hand, the bettor is required to pay to the gaming establishment a commission (typically 5%) of the amount the bettor wins. No commission is paid if the bettor successfully wagers on the player's hand.
As disclosed in this specification, the term "conventional manner of play of baccarat" is as follows:
A multiple number of decks of standard playing cards, 52 in number, are used; typically six to twelve decks are shuffled together and placed in a shoe from which the cards are dealt during the play of the game.
Each bettor makes a wager on whether the bank's hand or the player's hand will win. After all wagers are made, two cards are dealt from the shoe to the bank position and two cards are dealt from the shoe to the player's position on the table layout. The cards are turned face up and the value of the bank hand and the player hand is determined.
Aces count as one; kings, queens, jacks and tens count as zero and the other cards count as their respective face value. The suits (hearts, diamonds, spades and clubs) have no meaning in baccarat. The highest hand value in baccarat is nine. All hand values range from a low of zero to a high of nine. If when the cards are added together, the total of the hand exceeds nine, then the hand value is determined by subtracting ten from the total of the hand. For example, a seven and nine total sixteen, but the hand value is six. An Ace and a nine total ten, but the hand value is zero.
A two card total of eight or nine is called a "natural"; a two card total of zero is called a "baccarat". As will be explained hereafter, in certain situations in the play of the game, a third card will be dealt. The value of this third card is added to the total of the first two cards and a new hand value is established. Again, if the new hand total exceeds nine, the hand value is determined by subtracting ten from the total of the hand.
Prior to the deal, each bettor can make one of three wagers: 1) that the bank hand will win; 2) that the player hand will win; or 3) that the bank hand and the player hand will tie. Wagering locations are provided on the baccarat table layout. Whichever of the bank hand or the player hand is closest to a total of nine is the winner.
All winning bank hand wagers are paid off at odds of one-to-one and the house charges a five percent (5%) commission on the amount won by the bettor. For example, if a bettor wagers $100 on the bank hand and the bank hand wins, the bettor wins $100 and is charged a $5 commission on the amount that the bettor won. The bettor is not charged any commission on the amount of his wager.
All winning player hand wagers are paid off at odds of one-to-one and the bettor is not charged any commission on the amount of his winnings or his wager. Winning wagers on the tie hand bet are paid off at odds of eight-to-one (depending on the gaming establishment) and the bettor is not charged any commission on the amount of his winnings or his wager. If a tie hand occurs, all wagers on the bank hand and all wagers on the player hand are "pushes" and the amount wagered is returned to the bettor.
The play of baccarat typically uses three casino dealers to operate the game. The casino dealers jointly participate in the shuffling of the decks of cards. After the shuffle is completed, one of the players is typically asked to cut the decks using a plastic cut card. The dealer then separates and restacks the cards from the point of the cut and the dealer or a player then inserts the plastic cut card no less than fifteen cards from the ends of the stacked decks and the entire stacked decks are placed into a shoe from which the cards are dealt during the play of the game. When the inserted plastic cut card appears during play, the hand in progress is completed and that round of play then ends. The cards are reshuffled to prepare for the next round of baccarat.
In conventional baccarat, the bettors deal the cards used in the game. Initially, one of the casino dealers (called the "caller") passes the shoe to the bettor sitting in seat number "1" at the baccarat table. After all wagers have been made, the caller tells the bettor with the shoe to begin the deal. The bettor deals a first card to the caller, a first card to himself, a second card to the caller and a second card to himself. All cards are dealt face down. The two cards given to the caller represent the player hand and the two cards kept by the bettor who is dealing the cards represent the bank hand.
The caller than allows one of the other bettors to turn up the player's hand. Traditionally, this honor is given to the bettor who has made the largest wager. The bettor turns up the two cards of the player's hand and tosses them to the caller. The caller places these two cards face up in the table location designated for the "player hand" and the caller announces the point total of the player hand.
The bettor who has the shoe then turns over the cards of the bank hand and tosses these two cards to the caller. The caller places these two cards face up in the table location designated for the "bank hand" and the caller announces to point total of the bank hand. Depending on the point total of the player's hand and the bank's hand, one more card may be dealt to either the player's hand, the bank's hand or both. The rules for determining whether a third card is dealt are fixed rules, there is no discretion for either the player's hand or the bank's hand on whether a third card is dealt.
If either the player hand or the bank hand has a point total of eight or nine on the first two cards, no third card is dealt to either hand and the hand with the highest point total is the winner (or the hand is a tie, as the case may be). If neither the player hand or the bank hand has a point total of eight or nine, then there is a possibility of a third card draw.
The third card draw rules are as follows:
Rule #1: If the initial two card player hand has a point total of 0, 1, 2, 3, 4 or 5, draws a third card. If the initial two card player hand has a point total of 6 or 7, the player hand stands and does not receive a third card.
Rule #2: If the player hand stands and does not draw a third card, then the bank hand follows Rule #1. In other words, if the player hand has a point total of 6 or 7, the bank hand draws a third card on a point total of 0, 1, 2, 3, 4 or 5 and the bank hand stands on a point total of 6 or 7.
Rule #3: If the player hand draws a third card, the bank hand must draw or stand as follows:
______________________________________ Bank hand two Bank hand draws when the Bank hand stands when the card point total player's hand third card is: player's hand third card is: ______________________________________ 0, 1 or 2 Bank always draws -- 3 0, 1, 2, 3, 4, 5, 6, 7 or 9 8 4 2, 3, 4, 5, 6 or 7 0, 1, 8 or 9 5 4, 5, 6 or 7 0, 1, 2, 3, 8 or 9 6 6 or 7 0, 1, 2, 3, 4, 5, 8 or 9 7 -- Bank always stands ______________________________________
All third card draw determinations are automatically made by the caller who is skilled in the game of baccarat. When the rules of baccarat require a third card for the player hand, the caller will request a card for the player hand. After the player hand is completed, the bank hand is completed in the same fashion. The caller then declares which hand has the highest point total and declares that hand the winner (or the caller declares a tie hand as the case may be).
In conventional baccarat the bettor who acts as the dealer continues to deal the cards until the player hand wins. As soon as the player hand wins, it is customary to pass the shoe counterclockwise around the baccarat table to the next bettor so that each bettor has the opportunity to deal the cards. Any bettor may decline to deal the cards. The fact that one of the bettors is physically dealing the cards has no affect on the outcome of the game because the rules for drawing and standing do not allow any discretion on the part of the players.
However, the use of the standard elongated baccarat table has several drawbacks. For example, the typical baccarat table is elongated primarily to provide seating capacity for multiple players; however, due to business levels, it is often necessary to close down the table for lack of adequate play which results in loss of revenue. In gambling locations where space is limited, such as river boats, the amount of space a gaming establishment can provide becomes invaluable. In such instances, many casinos have been forced to resort to "mini-bac" tables which allow for approximately one-half the players and ultimately destroys the excitement of the game as the rules and play of the game have to be modified extensively. For instance, players are typically not allowed to handle the cards and pass the shoe from player to player.
Also, because the standard baccarat table is elongated, the table is typically formed with two betting areas on either end and a central area for player hand and bank hand placement. Four baccarat table operators are typically used to run a standard baccarat table, this would include three dealers (one of which is a caller), and a relief. The necessity of using four people to monitor the typical baccarat table lowers the profitability of these standard baccarat tables.
Since none of the players have any affect on how the cards are played, the most significant interaction or only interaction the players have in the game of baccarat is on placing bets. Therefore this game is not always an extremely popular gaming table at certain gaming establishments. Gaming establishments have provided additional wagering features on other types of games such as slot machines in order to entice players to make additional wagers and allow the players to win an additional reward from a "progressive" jackpot. Various modifications to the game of baccarat have been proposed in the past to eliminate the 5% house commission and provide for additional side wagers; however, none of these modifications have proven to be widely accepted or successful.
Furthermore, the standard baccarat tables and the mini-bac tables have a standard layout of numbers representing each player and also include betting boxes for wagering on a banker's hand, player's hand, and a tie. The aesthetic view of these table layouts is rather ordinary and plain and is not specifically designed to entice other people to play unless they understand how baccarat is played. In the case of using a larger baccarat table wherein three dealers are required, the layout of the table provides for betting areas on two opposite ends of the table. This particular layout can make it difficult for the dealers to adequately monitor all the bets since each dealer has to continually look to the sides to view the players' bets. This can cause confusion created by vague and unclear betting areas.
These and other types of baccarat games and table layouts disclosed in the prior art do not offer the flexibility and inventive features of our baccarat game method of play and apparatus. As will be described in greater detail hereinafter, the baccarat game method and table layout of the present invention differs from those previously proposed.

Casino progressive baccarat game method of play


A rule for use in conjunction with a cutting die and adapted to be received within an elongated slit formed in a die board. The rule includes an upper edge and a lower edge, and a main body extending between the lower and upper edges. A series of notches are generally uniformly formed and spaced about a lower portion of the rule such that the respective notches effectively extend through the lower edge of the rule and are open along the lower edge of the rule. The series or group of notches function to facilitate the curving of the rule and further function to bridge certain uncut sections of the die board that exist within one or more slits formed in the die board.

The present invention relates to rules used in conjunction with die boards and more particularly to a rule design having a group of notches formed in the lower portion thereof where the notches serve to bridge portions or sections of the die board.
Various types of rules are customarily used in cutting dies. In the way of examples, these rules may include perforating, scoring or cutting rules. In any event, these rules are typically inserted within slits formed in a die board that forms a part of a cutting die. Typically a die board is designed such that it extends over a cylinder or plate structure and these slits extend completely through the die board such that once a rule is inserted therein, the rule may in fact engage the underlying cylinder or plate structure. In order to keep the die board together and prevent the die board from falling apart like a puzzle, it is customary to leave sections of the slit uncut. It is appreciated that the rules will have to be notched in order that they might be able to bridge these uncut sections within the slits. To deal with this, it is customary for a die maker to cut bridging notches in the lower portion of the rules before inserting them into the respective slits of the die board. That is, the die maker will typically measure the slits and determine precisely the locations of the uncut sections within the slits that have to be bridged. Once this is done, then the die maker will proceed to cut bridging notches in the lower portions of the rule such that the bridging will appropriately line-up with the uncut sections that lie in the slits of the die board. However, it is no small undertaking to cut bridge notches in a set of rules. Indeed, it is not unusual for a typical rotary die board used for cutting corrugated board, for example, to include 700 inches of rule and approximately 200 individual bridges or notches formed in the rule. Not only are there many notches to be cut, but each individual notch or bridge requires substantial time and effort on the die maker""s part. Cutting bridge notches in rules is for the most part a laborious manual operation that requires a substantial amount of time and effort. Furthermore, in cutting bridge notches in rules, the bridge notch usually is formed in a square or rectangular configuration. When such bridge notches are introduced into the rule, there is also introduced new stress points about the upper corners of the bridge notches.
Further, it should be appreciated that in the case of rotary die cutting machines, the die board assumes a generally arcuate or curved configuration. Accordingly, it is not unusual for the rules, whether they be perforating, scoring or cutting rules, to be curved or arcuate shaped. To facilitate the curving of these rules, it is common practice to cut very small notches in the lower portion of rules prior to the rules actually being curved. That is, the rules are ordinarily fabricated in a straight configuration. Thereafter, the small notches are formed in the lower portion of the rules and thereafter the rules are curved. The presence of the small notches in the lower portion of the rules generally facilitates the curving of the rules.
The present invention entails a rule for a cutting die that includes preformed bridging notches that are generally uniformly spaced to span uncut sections of slits formed in a die board. More particularly, the rule includes an upper edge, lower edge, and a main body extending between the upper and lower edges. The bridging notches extend through the lower edge into the main body of the rule. Consequently, the bridge notches are opened from the bottom or along the lower edge of the rule.
The bridge notches may form any one of a number of functions. First, the notches may facilitate the formation of a curved rule. That is, in forming a curved or arcuate-shaped rule, that process or method begins with forming a straight or horizontal rule and then curving the rule. By forming notches within the lower portion of the straight rule, the straight rule is easier to curve.
Secondly, these rules are designed to fit within the slits cut within a die board of a cutting die. Because the slits are normally open to an underlying cylinder or plate, for example, it is important that sections within the slits remain uncut so as to hold the die board together and keep the die board from falling apart like a puzzle. However, these uncut sections appearing at intervals within a slit must be bridged or spanned when the rule is inserted therein. Thus, these bridging notches formed in the lower portion of the rule function to span the uncut sections that lie at selective intervals along the slits.
Other objects and advantages of the present invention will become apparent and obvious from a study of the following description and the accompanying drawings which are merely illustrative of such invention.