The invention relates to compounds of the formula 1, 2, and 3

This invention relates to novel tricyclic erythromycin derivatives. The compounds of this invention are useful as antibiotic agents in mammals, including man, as well as in fish and birds. The compounds of the present invention are broad-spectrum macrolide antibiotics that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa. Various derivatives of erythromycin A, useful as antibiotic agents, are referred to in U.S. patent application Ser. No. 60/049,349, filed Jun. 11, 1997, and U.S. application Ser. No. 09/355092, filed Jul. 20, 1999, both of which are incorporated herein by reference in their entirety, and in U.S. patent application Ser. No. 60/063,676, entitled xe2x80x9c9-Amino-3-Keto Erythromycin Derivativesxe2x80x9d, (Yong-Jin Wu), filed Oct. 29, 1997, which is incorporated herein by reference thereto, in its entirety.
The present invention relates to compounds of the formula I
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
R is C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, or C3-C10 cycloalkyl, wherein up to two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substituents), said substituents being selected from the group (hereinafter also referred to as xe2x80x9cGroup Axe2x80x9d) consisting of:
(a) nitro;
(b) N3;
(c) CN;
(d) C1-C10 alkoxy;
(e) C1-C10 alkanoyl;
(f) C1-C10 alkyl;
(g) C2-C10 alkenyl;
(h) C2-C10 alkynyl;
(i) C3-C10 cycloalkyl;
(j) 4 to 10 membered heterocyclic;
(k) xe2x80x94C(O)R10;
(l) xe2x80x94C(O)OR10;
(m) xe2x80x94NR10R11;
(n) xe2x80x94NHC(O)R10;
(o) xe2x80x94NHC(O)NR10R11;
(p) xe2x80x94S(O)n, wherein n is 0,1, or 2;
(q) xe2x80x94SO2R10; and
(r) xe2x80x94SO2NR10R11;
each R1, R2, R3, and R4 is independently selected from H, C1-C12 C3-C10 alkenyl, C3-C10 alkynyl, and xe2x80x94(CR8R9)mZ, with m being an integer from 0 to 6; wherein up to two carbons of said alkyl, alkenyl, alkynyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by one or more substituents (preferably from one to four substituents), selected from Group A;
or R2 and R3, together with the carbon to which they are attached, form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N;
R5 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94Z, and xe2x80x94(CR9R10)mZ; with m being an integer from 1 to 6; wherein the alkyl, alkenyl and alkynyl can be substituted with one or more substituents (preferably from one to four substituents) selected from Group A;
R6is H, xe2x80x94C(O)O(C1-C18) alkyl or xe2x80x94C(O)(C1-C18) alkyl, wherein one or more carbons of either of said alkyl may be replaced by a heteroatom selected from O, S and N;
each R8 and R9 is independently selected from H, halo, and C1-C6 alkyl; or R8 and R9, together with the carbon to which they are attached, can form a 3 to 10 membered cyclic or heterocyclic di-radical;
each R10 and R11 is independently H, C1-C12 alkyl, aryl substituted C1-C12 alkyl, or heteroaryl substituted C1-C12 alkyl, wherein one or more carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N.
each Z is independently 4-10 membered heterocyclic or C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A;
T is absent or selected from the group consisting of:
(a) xe2x80x94C(O)xe2x80x94,
(b) xe2x80x94C(O)xe2x80x94Oxe2x80x94,
(c) xe2x80x94CH2xe2x80x94,
(d) xe2x80x94C(S)xe2x80x94Sxe2x80x94,
(e) xe2x80x94C(O)xe2x80x94NR10xe2x80x94;
(f) xe2x80x94S(O)nxe2x80x94, where n is 0,1, or 2,
(g) xe2x80x94S(O)nxe2x80x94Oxe2x80x94, wherein n is 0, 1, or 2,
(h) xe2x80x94P(O)(OR10)nxe2x80x94, wherein n is 0, 1, or 2, and
(i) xe2x80x94S(O)2xe2x80x94NR10xe2x80x94,
Rt is selected from the group consisting of: C1-C6 alkyl, C3-C6 alkenyl, C3-C12 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A.
The present invention also relates to compounds of formula 2:
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
each Rw and Rx is independently H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, or C3-C10 cycloalkyl, wherein up to two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substitutents) selected from Group A;
R1 is as defined for formula 1, or R1 and Rw together with the nitrogen to which they are attached can form xe2x80x94Nxe2x95x90C(R1)(R2), or form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N,
R4 is as defined for formula 1, or R4 and Rx, together with the nitrogen to which they are attached, form xe2x80x94Nxe2x95x90C(R4)(R2), or form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N,
R, R5, R6, Rt and T are as defined for formula 1.
The present invention also relates to compounds of formula 3:
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
Rw is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C10 cycloalkyl, wherein one or two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably 1-4 substitutents) selected from Group A;
Rz is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C10 cycloalkyl, wherein one or two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A;
R, R1, R5, R6, Rt and T are as defined for formula 1.
A first embodiment of the invention is a compound having the formula 1, as described above, and a preferred embodiment is a compound of formula 1 wherein R=Et, R2=R3=R4=R6=H, R5=Me, and R1=xe2x80x94(CH2)3Z.
Representative compounds of the invention having formula 1 are those selected from the group consisting of:
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rtis (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R1=Me, R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-y, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R1=Me, R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R1=Me, R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R4=Me, R1=R2=R3=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R4=Me, R1=R2=R3=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R4=Me, R1=R2=R3=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R2=R3=Me, R1=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R2=R3=Me, R1=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R2=R3=Me, R1=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, TT is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is (4-methoxy)benzoyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is methanesulfonyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CHxe2x95x90CH2,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2N(CH3)2,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2xe2x80x94S-phenyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is (2-nitrophenyl),
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is phenyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)NHxe2x80x94, Rt is allyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is CH(CH3)2,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is cyclohexyl,
the pharmaceutically acceptable salts and prodrugs of the foregoing compounds.
A second embodiment of the invention is a compound having the formula 2 as described above and a preferred embodiment is a compound of formula 2 wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z.
Representative compounds of the invention having formula 2 are those selected from the group consisting of:
Compounds of formula 2, wherein R=Et, R1=Rw=Rx=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl
Compounds of formula 2, wherein R=Et, R1=Rw=Rx=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 2, wherein R=Et, R1=Rw=Rx=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is (4-methoxy)benzoyl,
Compounds of formula 2, wherein Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is methanesulfonyl,
Compounds of formula 2, wherein Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CHxe2x95x90CH2,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2N(CH3)2,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2xe2x80x94S-phenyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is (2-nitrophenyl),
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is phenyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)NHxe2x80x94, Rt is allyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is CH(CH3)2,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is cyclohexyl,
the pharmaceutically acceptable salts and prodrugs of the foregoing compounds.
A third embodiment of the invention is a compound having the formula 3 as described above and a preferred embodiment is a compound of formula 3 wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z.
Representative compounds of the invention having formula 3 are those selected from the group consisting of:
Compounds of formula 3, wherein R=Et, R1=Rw=R6=H, Rz=Me, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 3, wherein R=Et, R1=Rw=R6=H, Rz=Me, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 3, wherein R=Et, R1=Rw=R6=H, Rz=Me, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, CH(CH3)2, or cyclohexyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is (4-methoxy)benzoyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is methanesulfonyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CHxe2x95x90CH2,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, R1 is xe2x80x94CH2CH2N(CH3)2,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is CH2CH2xe2x80x94S-phenyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is (2-nitrophenyl),
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is phenyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is allyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is xe2x80x94CH(CH3)2,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is cyclohexyl,
the pharmaceutically acceptable salts and prodrugs of the foregoing compounds.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formulas 1-3, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formulas 1-3 or a pharmaceutically acceptable salt or prodrug thereof.
The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention.
The invention also relates to a method of preparing compounds of formulas 1-3
and pharmaceutically acceptable salts thereof, wherein R, R1-R6, Rt and T are as defined above. The compound of formula 1 is prepared as follows: treating a compound of the formula 7
with a compound of formula R2R3C(xe2x95x90O) in the presence of an acid in a solvent. The preferred acids are formic acid, acetic acid, p-toluenesulfonic acid and the preferred solvents are THF, dichloromethane, and chloroform.
Patients that can be treated with the compounds of formulas 1-3, and/or the pharmaceutically acceptable salts and prodrugs thereof, include mammals (particularly humans), fish, and birds suffering from infections caused by various micro-organisms including Gram positive and Gram negative bacteria.
As used herein, unless otherwise indicated, the term xe2x80x9cbacterial infection(s)xe2x80x9d or xe2x80x9cprotozoa infectionsxe2x80x9d includes bacterial infections and protozoa infections which occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chiamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory diseases related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., xe2x80x9cThe Sanford Guide To Antimicrobial Therapy,xe2x80x9d 26th Edition, (Antimicrobial Therapy, Inc., 1996).
In the chemical structures depicted herein, a wavy line indicates that the stereochemistry at the chiral center to which the wavy line is connected is either an R or S configuration where the wavy line is connected to a carbon atom. In the compound of formula 3, the wavy line connected to the oxime nitrogen at position 9 of the macrolide ring indicates that the xe2x80x94ORz moiety is in an E or Z configuration.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties. Said alkyl group may include one or two double or triple bonds. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group.
The term xe2x80x9calkanoylxe2x80x9d, as used herein, unless otherwise indicated, includes xe2x80x94C(O)-alkyl groups wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
As used herein, unless otherwise indicated, xe2x80x9cAcxe2x80x9d indicates an acetyl group.
As used herein, unless otherwise indicated, xe2x80x9cMexe2x80x9d indicates a methyl group.
The term xe2x80x9c4-10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 5 membered heterocyclic group is thiazolyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. In general, acceptable 4-10 membered heterocyclic groups include those derived from one of the following: furan, thiophene, 2H-pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole, 2-imidazole, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, 2H-pyran, 4H-pyran, pyridine, piperidine, 1,4-dioxane, 1,3-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, 1,3,5-triazine, 1,3,5-trithiane, indolizine, indole, isoindole, 3H-indole, indoline, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, quinuclidine, carbazole, acridine, phenazine, phenothiazine, phenoxazine, tetrazole, thietane and azetidine.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I-3. The compounds of formula I-3 that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula I3 that are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts.
The present invention also includes all radio-labeled forms of the compounds of formula 1-3, and pharmaceutically acceptable salts thereof, wherein the radio-label is selected from 3H, 11C and 14C. Such radio-labeled compounds are useful as research or diagnostic tools.
Certain compounds of formula 1-3 may have asymmetric centers and therefore exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of formula 1 and mixtures thereof. In particular, the invention includes both the R and S configurations of C-2 and C-10 the macrolide ring of formula 1-3. The compounds of formula 1-3 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The preparation of the compounds of the present invention is illustrated in the following Schemes 1 to 5.
Scheme 1 depicts the general synthesis of compound of formula 1. The synthesis of compound 4 is disclosed in U.S. provisional patent application No. 60/106,798, filed Nov. 3, 1998, which is incorporated herein in its entirety by reference thereto. Exposure of compound 4 to acidic conditions can effect the cleavage of the cladinose sugar to give the compound of formula 5. The preferred acidic condition is HCl in ethanol. The reduction of 9-hydroxyimino group of the compound of formula 5 can be effected by treating the starting compound with a reducing agent such as TiCl3 in a polar solvent such as methanol. The resulting imine of formula 6 can be converted to the corresponding amine of formula 7, by means of reduction with a reducing agent such as NaBH3CN in a polar solvent such as methanol. The conversion of the compound of formula 7 to formula 8 can be effected by following substantially the same procedures as described in PCT publication WO 9921865 (Pfizer. Inc.,Yong-Jin Wu), to wit, by treatment of the compound of formula 7 with R2R3Cxe2x95x90O in the presence of an acid catalyst such as acetic acid to PTSA (p-toluenesulfonic acid), in a solvent such as ethanol or toluene, at a temperature within the range of 40 to 80 degrees C. for a period of 1 to 24 hours. Compounds of formula 8 can be converted to that of formula 9 through alkylation or reductive alkylation by methods known to one skilled in the art. Compounds of formula 1 can be prepared from compounds of formula 9 by many methods known to those skilled in the art.
Scheme 2 describes an alternative synthesis of the compound of formula 5. The starting compound of formula 10 is disclosed in PCT publication WO97/31929. Compounds of formula 10 can be converted to that of formula 11 by treating the compound of formula 10 with acidic conditions followed by methanol. The preferred acidic condition is HCl in ethanol. Oximation of the compound of formula 11 can be carried out by methods known to those skilled in the art. The preferred oximation condition is hydroxylamine hydrochloride and pyridine in n-butanol at 70-90xe2x96xa1C. The conversion of the compound of formula 12 to the compound of formula 5 can be effected by direct alkylation or reductive alkylation using methods known to one skilled in the art.
Scheme 3 describes a general synthesis of compounds of formula 2. The starting compound of formula 7 is available from Scheme 1. Compound 7 can be converted to 13 through reductive alkylation or direct alkylation by a variety of methods known to those skilled in the art. Compounds of formula 2 can be synthesized from those of 13 by many methods known to one skilled in the art.
Scheme 4 depicts the general synthesis of compound of formula 3 wherein the starting compound of formula 10 is disclosed in PCT publication WO97/31929. Compounds of formula 14 can be synthesized from the compound of formula 10 by treatment with RzONH2.HCl and base in a solvent, preferably at a temperature from 50 to 100xc2x0 C. Preferred bases include, but are not limited to, triethylamine, 2,6-lutidine, 1,8-diazabicyclo95.4.0)undec-7-ene (DBU), and N,N-diethylpropylamine. Preferred solvents include, but are not limited to, acetonitrile, methanol, ethanol, and n-butanol. The conversion of the compound of formula 14 to the compound of formula 15 can be effected through alkylation or reduction alkylation using methods known to those skilled in the art. Alternatively, compounds of formula 15 can be derived from compounds of formula 16. The synthesis of compounds of formula 16 is disclosed in U.S. provisional patent application No. 60/106,798, filed Nov. 3, 1998, which is incorporated herein in its entirety by reference thereto. Compounds of formula 15 can be synthesized from compounds of formula 16 by treatment with RzONH2.HCl and base in a solvent, preferably at a temperature from 50 to 100xc2x0 C. Preferred bases include, but are not limited to, triethylamine, 2,6-lutidine, 1,8-diazabicyclo95.4.0)undec-7-ene (DBU), and N,N-diethylpropylamine. Preferred solvents include, but are not limited to, acetonitrile, methanol, ethanol, and n-butanol. The transformation from the compounds of formula 16 to compounds of formula 3 can be achieved by many methods known to one skilled in the art.
Scheme 5 describes the synthesis of a compound of formula 3, wherein Rw is H, R6 is H, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, as shown by the compound of formula 19. Compounds of formula 17 can be prepared from 15, wherein Rw is hydrogen. Compounds of formula 18 can be prepared by treatment the compound of formula 17 with a compound of formula Rtxe2x80x94Nxe2x95x90Cxe2x95x90O in a solvent such as toluene in the presence of a base such as 4-dimethylaminopyridine (DMAP) at 30-110xc2x0 C. The conversion of the compound of formula 18 to the compound of formula 19 can be effected by treatment with methanol at 50-70xc2x0 C.
The compounds of the present invention may have asymmetric carbon atoms. Such diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomer mixtures and pure enantiomers are considered as part of the invention.
The compounds of formula 1-3 that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply converting the latter back to the free base compound by treatment with an alkaline reagent and subsequently converting the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
Those compounds of the formulas I-3 which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts may be prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula 1-3. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The activity of the compounds of the present invention against bacterial and protozoa pathogens is demonstrated by the compound""s ability to inhibit growth of defined strains of human (Assay I) or animal (Assays II and III) pathogens.
Assay I, described below, employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that may lead to compounds that circumvent defined mechanisms of macrolide resistance. In Assay I, a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized. Use of this panel enables the chemical structure/activity relationship to be determined with respect to potency, spectrum of activity, and structural elements or modifications that may be necessary to obviate resistance mechanisms. Bacterial pathogens that comprise the screening panel are shown in the table below. In many cases, both the macrolide-susceptible parent strain and the macrolide-resistant strain derived from it are available to provide a more accurate assessment of the compound""s ability to circumvent the resistance mechanism. Strains that contain the gene with the designation of ermA/ermB/ermC are resistant to macrolides, lincosamides, and streptogramin B antibiotics due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, thereby generally preventing the binding of all three structural classes. Two types of macrolide efflux have been described; msrA encodes a component of an efflux system in staphylococci that prevents the entry of macrolides and streptogramins while mefA/E encodes a transmembrane protein that appears to efflux only macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by either a phosphorylation of the 2xe2x80x2-hydroxyl (mph) or by cleavage of the macrocyclic lactone (esterase). The strains may be characterized using conventional polymerase chain reaction (PCR) technology and/or by sequencing the resistance determinant. The use of PCR technology in this application is described in J. Sutcliffe et al., xe2x80x9cDetection Of Erythromycin-Resistant Determinants By PCRxe2x80x9d, Antimicrobial Agents and Chemotherapy, 40(11), 2562-2566 (1996). The antibacterial assay is performed in microtiter trays and interpreted according to Performance Standards for Antimicrobial Disk Susceptibility Testsxe2x80x94Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitory concentration (MIC) is used to compare strains. acr AB or acr AB-like indicates that an intrinsia multidrug efflux pump exists in the strain. Compounds are initially dissolved in dimethylsulfoxide (DMSO) as 40 mg/ml stock solutions.
Assay II is utilized to test for activity against Pasteurella multocida and Assay III is utilized to test for activity against Pasteurella haemolytica.
This assay is based on the liquid dilution method in microliter format. A single colony of P. multocida (strain 59A067) is inoculated into 5 ml of brain heart infusion (BHI) broth. The test compounds are prepared by solubilizing 1 mg of the compound in 125 xcexcl of dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used range from 200 xcexcg/ml to 0.098 xcexcg/ml by two-fold serial dilutions. The P. multocida inoculated BHI is diluted with uninoculated BHI broth to make a 104 cell suspension per 200 xcexcl. The BHI cell suspensions are mixed with respective serial dilutions of the test compound, and incubated at 37xc2x0 C. for 18 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of growth of P. multocida as determined by comparison with an uninoculated control.
This assay is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated into BHI broth and incubated overnight at 37xc2x0 C. with shaking (200 rpm). The next morning, 300 xcexcl of the fully grown P. haemolytica preculture is inoculated into 3 ml of fresh BHI broth and is incubated at 37xc2x0 C. with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of two-fold serial dilutions are prepared. Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. haemolytica culture reaches 0.5 McFarland standard density, about 5 xcexcl of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37xc2x0 C. Initial concentrations of the test compound range from 100-200 xcexcg/ml. The MIC is equal to the concentration of the test compound exhibiting 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control.
The in vivo activity of the compounds of formula (I) can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in mice.
Mice are allotted to cages (10 per cage) upon their arrival, and allowed to acclimate for a minimum of 48 hours before being used. Animals are inoculated with 0.5 ml of a 3xc3x97103 CFU/ml bacterial suspension (P. multocida strain 59A006) intraperitoneally. Each experiment has at least 3 non-medicated control groups including one infected with 0.1xc3x97challenge dose and two infected with 1xc3x97challenge dose; a 10xc3x97challenge data group may also be used. Generally, all mice in a given study can be challenged within 30-90 minutes, especially if a repeating syringe (such as a Cornwall(copyright) syringe) is used to administer the challenge. Thirty minutes after challenging has begun, the first compound treatment is given. It may be necessary for a second person to begin compound dosing if all of the animals have not been challenged at the end of 30 minutes. The routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered into the loose skin in the back of the neck whereas oral doses are given by means of a feeding needle. In both cases, a volume of 0.2 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, and 24 hours after challenge. A control compound of known efficacy administered by the same route is included in each test. Animals are observed daily, and the number of survivors in each group is recorded. The P. multocida model monitoring continues for 96 hours (four days) post challenge.
The PD50 is a calculated dose at which the compound tested protects 50% of a group of mice from mortality due to the bacterial infection which would be lethal in the absence of drug treatment.
The compounds of formula 1-3 and their pharmaceutically acceptable salts or prodrugs (hereinafter referred to, collectively, as xe2x80x9cthe active compounds of this inventionxe2x80x9d) may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compounds of this invention can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration, solutions containing an active compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
To implement the methods of this invention, an effective dose of an active compound of this invention is administered to a susceptible or infected animal (including mammals, fish and birds) by parenteral (i.v., i.m. or s.c.), oral, or rectal routes, or locally as a topical application to the skin and/or mucous membranes. The route of administration will depend on the mammal, fish or bird that is being treated. The effective dose will vary with the severity of the disease, and the age, weight and condition of the animal. However, the daily dose will usually range from about 0.25 to about 150 mg/kg body weight of the patient to be treated, preferably from about 0.25 to about 25 mg/kg.
The Examples provided below illustrate specific embodiments of the invention, but the invention is not limited in scope to the Examples specifically exemplified.

Abstract: and to pharmaceutically acceptable salts and prodrugs thereof, wherein the groups are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula I, methods of using said compounds of formula 1, 2, and 3 the treatment of infections, and methods of preparing said compounds of formula 1, 2, and 3.


The air-conditioning system comprises a dryer (10) comprising a membrane contactor (11) provided with a first channel (11b) for air flow and a second channel (11a) for desiccant flow, which channels are separated through a membrane (11c). The air conditioning system further comprises a humidifier (20) comprising a membrane contactor. The air flow passes in operation the dryer (10) and the humidifier (30) between an inlet (121) and an outlet (122). The dryer (10) comprises a series connection of a heat exchanger (12) and the membrane contactor (11), which heat exchanger couples air flow from the inlet (121) with desiccant flow from a regenerator (40) and in which membrane contactor (11) the thus heat-exchanged air flow and the heat-exchanged desiccant flow are coupled for drying of the airflow.

Air-conditioning system that operate on the basis of mass and heat exchange over so-called membrane contactors receive attention in an attempt to improve efficiency. Basically, such systems comprise a dryer, a humidifier and a regenerator. Schematic diagrams hereof look rather simple, though the understanding of the operation is rather complex. In fact, such systems are multi-phase and multi-chamber reactor in which mass and heat transfer occurs. An additional complicating factor resides in the desiccant flow: if the solution of desiccant becomes too concentrated, crystals may develop which may reduce the mass transfer in the membrane contactor or even obstruct the desiccant flow. However, relatively high concentrations of desiccant are desired for efficient operation of the system. A further complicating factor resides therein that different locations in the world require significantly different air treatments, so as to arrive in a so-called comfort zone that is appreciated by most people.
One example of an air-conditioning system is known from U.S. Pat. No. 6,887,302. This document proposes the use of a metering device configured to add water so as to increase the water content of the desiccant flow, as well as a control device therefor. By means of adding water to the desiccant flow, the operation of the membrane contactor could be modified, so as to switch between humidification en dehumidification. This known solution however is disadvantageous energetically, as it is very hard to remove again water from the desiccant flow once needed. Moreover, the addition of water is effectively a thinning of the desiccant flow, but it is not evident to obtain a homogeneous solution quickly.
Another example of an air-conditioning system is known from WO2009/094032A1. That prior document discloses a module design wherein flow of cooling fluid, desiccant flow and air flow are integrated into a single multilevel module. As shown in FIG. 1, the air flow (inlet airstream) runs in parallel to the liquid desiccant flow. This reduces the overall both heat and mass transfer efficiency relative to a countercurrent flow design.
A further example of an air-conditioning system is known from manuscripts of Dr Manuel Conde-Petit, particularly 'Open absorption systems for air-conditioning using membrane contactors', 15. Schweizerisches Status-Seminar<<Energie-and Umweltforschung im Bauwesen>>, 11-12 Sep. 2008 in Zurich, and 'Open absorption system for cooling and air conditioning using membrane contactors, 2006 Annual report' for the Swiss Government. For sake of clarity, these publications will be referred to as the 2008 report and the 2006 report respectively.
Conde herein proposes a modular design. FIGS. 12 and 13 of the 2008 report show the system that has been designed, made and tested. FIG. 3 of the 2008 report shows a more elaborate diagram. As is clear from FIG. 12, the system is provided with a first air inlet for the air to be treated and a second air inlet for use as a gas flow in the regenerator. The air from the regenerator is removed as an air exhaust. The regenerator unit further comprises a heat exhanger, wherein inlet air is cooled relative to the exhaust air that has passed the regenerator. Both the dryer, referred to as ABS or absorber, and the regenerator, referred to as GEN or desorber, are operated as three-stream contactors of air flow, desiccant flow and water. The 2008 report thereto states that it was clear 'from the beginning that a continuously cooled absorber and a continuously heated desorber would be necessary in the prototype to be built'.
The three-stream membrane contactor is shown in more detail in the 2006 report. It is built out of five structured plates that may be of equal or different size (cross-section), where the membrane constitutes the interface between the air channels and the solution channels. The air flow and the water flow run in a countercurrent manner in parallel channels. The desiccant flow runs in channel extending substantially perpendicular to those for the air flow and the water flow. The structured plates are made of polymer material and are modified by milling, after having been cut to the right size. Due to the small wall thickness of the plates (0.1-0.3 mm), this was delicate according to the 2006 report. Thereto the structured plates were filled with water and freezed on top of a thermally conducting metallic plate. The frozen plate was thereafter milled, using the metallic plate as a carrier. The delicate multi-step manufacturing is a clear disadvantage of the modules used by Conde. It is therefore desired to obtain an improved air-conditioning system with modules that may be made more easily, but still meeting the requirements of the overall process in operation. In fact, said modules were designed by Conde for optimum mass and heat transfer, as deemed necessary to achieve the continuous cooling or heating as deemed necessary.


An apparatus for facilitating the connection of tubulars, said apparatus comprising a winch, at least one wire line, and a device for gripping the tubular, the arrangement being such that, in use, the winch can be used to winch said at least one wire and said device to position a tubular below said top drive.

1. Field of the Invention
This invention relates to a method and apparatus for facilitating the connection of tubulars using a top drive and is, more particularly but not exclusively, for facilitating the connection of a section or stand of casing to a string or casing.
2. Description of the Related Art
In the construction of wells such as oil or gas wells, it is usually necessary to line predrilied holes with a string of tubulars known as casing. Because of the size of the casing required, sections or stands of say two sections of casing are connected to each other as they are lowered into the well from a platform. The first section or stand of casing is lowered into the well and is usually restrained from falling into the well by a spider located in the platform's floor. Subsequent sections or stands of casing are moved from a rack to the well centre above the spider. The threaded pin of the section or stand of casing to be connected is located over the threaded box of the casing in the well to form a string of casing. The connection is made-up by rotation therebetween.
It is common practice to use a power tong to torque the connection up to a predetermined torque in order to perfect the connection. The power tong is located on the platform, either on rails, or hung from a derrick on a chain. However, it has recently been proposed to use a top drive for making such connection.
Prior to the present invention, pipe handling devices moved pipes to be connected to a tubular string from a rack to the well centre using articulated arms or, more commonly, a pipe elevator suspended from the drilling tower.
The present invention provides an alternative to these devices.

Method and apparatus for connecting tubulars using a top drive


A stock stop for screw machines and the like for determining bar stock positioning and which is capable of sensing short stock. The stock stop includes a housing affixed to the machine tool having a slidable sleeve in which a threaded stop is adjustably positioned. A spring biases the sleeve and stop toward the advancing bar and the sleeve is displaced to a stop position by the advancing bar stock. Motion multiplying means multiply the sleeve movement upon engagement by the bar stock to actuate a proximity switch indicating proper advancement of the bar stock and permitting continued machine tool operation. As the components of the stock stop are encased and protected against contamination, a high degree of reliability is attained while providing accurate machine tool control with respect to the presence of adequate bar stock for machining.

1. Field of the Invention
The invention pertains to bar stock stops for turning machines and particularly relates to bar stock stops automatically disabling the machine tool in the event of "short" stock.
2. Description of the Related Art
Stock stops for turning machines have long been used in the machine tool art and various types of stock stops of a more complex type are shown in U.S. Pat. Nos. 4,187,748; 5,033,339; 5,642,650; and 5,676,031.
However, while stock stops are available utilizing electric sensors or pneumatic or hydraulic actuating systems, such stock stops are expensive, complicated, and not as dependable as desired. Stock stops limit the axial feeding motion of bar stock prior to machining, and if insufficient bar stock length exists to properly axially position the bar stock prior to machining, damage may result to the machine tool, or a complete cycle of machining will occur producing a non-compliance part resulting in low productivity. In particular, the damage that may result from short bar stock renders the desirability of an inexpensive, dependable short stock sensing stop highly significant.


The present invention relates to compositions comprising polypeptides and polysaccharides. The compositions are in general immune modulating. The invention also discloses methods of producing these compositions using filamentous fungi cultivated in liquid medium. The compositions are useful for example in the treatment of immune compromised conditions.

It is known that health-promoting effects are attributed to glucans from fungi and yeasts. "Shiitake" fungus (Lentinus edodes) has been attributed effects which can be exploited for many medicinal purposes such as immunestimulation, anti-virus, anti-tumor, etc. Studies of lentinan have shown that it stimulates the immune system of the host in a variety of ways, such as activation of T helper cells, increased production of Interleukin 1 and Interleukin 2, increased antibody production in various forms of cancer, and decreasing the cholesterol level in the blood. (Herbs for Health, January/February, 1997; K. Jones, "Shiitake: Medicine in a mushroom", p. 40-50, 54; Anticancer Res, Vol. 17(4A), 1997; H. Matsouka, "Lentinan potentiates immunity and prolongs the survival time of some patients", p. 2751-2755; Adv Appl Microbiol, Vol. 39, 1993; S. C. Jong, "Medicinal and therapeutic value of the shiitake mushroom", p. 153-184, Int J Immunopharmacol, Vol. 14, 1992; K. Irinoda, "Stimulation of microbiocidal host defense mechanism against aerosol influenza virus infection by lentinan, p. 971-977, Jpn J Cancer Res, Vol. 76(1), 1985; D. Herlyn, "Monoclonal antibody-dependent murine macrophage-mediated cytotoxicity against human tumors is stimulated by lentinan, p. 37-42).
One active ingredient of Lentinus edodes is termed lentinan, a polysaccharide based compound described as a beta-(1,3) glucan backbone with beta-(1,6) side chains.
"Solid-state" reactors are routinely used for culturing fungi such as Lentinus edodes. This is a technology which is used for many purposes such as composting, production of biological products such as enzymes, soy sauce, acetic acid, and the like. For the production of lentinan, Lentinus edodes can be cultivated on a suitable solid matrix provided by stems of tree or chips of wood to which is often added chemical compounds supporting the growth of mycelium and development of the fruiting bodies, where most of the lentinan is localised. The fruiting bodies are harvested, either by hand or mechanically, and are subsequently dried and ground to a powder which can be used as it is, or used in tablets, or sent for further processing such as extraction of lentinan.
A polysaccharide product prepared from Lentinus edode is commercially available as "Lentinan for injection" (Eureka Bio-Chemicals Pty, Australia). This product has some immunestimulating effect (see also the examples herein below).
The patent application WO03/020944 describes a number of methods of purifying extracellular immunestimulating compounds from fungi. In general these methods involve a precipitation step.
However, compositions with very high immunestimulating activity have not been disclosed. It is therefore an object of the present invention to provide novel compositions, preferably extracellular immune stimulating agents from fungi with high level of immune modulating activity.

This patent is subject to a terminal disclaimer.


Methods and structure for switching heads on a multiple recording surface disk drive that uses bi-directional radial writing toward a zipper zone at a middle diameter. When switching from a first head to a second head, features and aspects hereof assure that the second head will not be positioned in the zipper zone of the corresponding second surface and hence will not lose track following servo synchronization and control. In one aspect, added buffer or guard tracks having valid servo information but no data are added on either side of the zipper zone to assure that under the worst-case misalignment of surfaces the second head will not be positioned in its corresponding zipper zone when switching from the first head.

1. Field of the Invention
The present invention relates generally to disk drive head switching and track following servo operation and more specifically relates to methods and structures for assuring that switching from a first head to a second head cannot leave the second head in a "zipper zone" of its corresponding surface to thereby lose track following synchronization.
2. Discussion of Related Art
Computing storage subsystems generally utilize rotating, magnetic, disk storage devices for rapid, random access to large volumes of stored data. In general, stored information on a rotating magnetic disk drive comprises magnetic flux density changes recorded around the circumference of concentric tracks positioned radially from the inner diameter (ID) of a disk media recording surface to the outer diameter (OD) of a disk media surface. Present day disk drives typically include a plurality of such recording media stacked on a common rotating spindle and each with a corresponding read/write head for recording information on the corresponding magnetic recording surface and for sensing previously recorded data therefrom. The plurality of read/write heads are typically arranged on actuator arms. A plurality of such arms are typically arranged in a comb-like structure between the various disk recording surfaces such that a read/write head is "flying" adjacent its corresponding recording media surface. The comb-like structure is actuated so that all read/write heads may be radially positioned to a particular concentric track. The read/write head associated with each disk drive recording media surface is therefore moved in unison with all other read/write heads. In other words, each read write head is positioned over substantially the same concentric track position—each on its corresponding magnetic recording surface. Though each of the heads of the comb-like structure may be roughly positioned to a common radial track position, the head position must be finely tuned while in use to more accurately position the head for reading or writing on the desired track. Servo control information may be pre-written on the disk media recording surface at various points about the circumference of each track to identify the track position of each concentric track (e.g., the track number and other relevant information regarding the track). The servo control information is read from the head and processed to allow a servo control mechanism to finely tune the radial position of the head relative to the center of the track as data is being read or written by the head on that track. To allow this fine tuning of radial position based on recorded servo information on each track, only one head is used at a time and the disk drive controller logic switches between multiple heads as needed to read or write the requested blocks of data.
It is common in disk storage systems to switch from one recording head to another recording head while reading or writing to avoid time consuming mechanical delays (latency) associated with radially repositioning the comb-like structure of multiple read/write heads and the delay in allowing the mechanism to settle at its new radial position. Switching from one head to another head incurs no such mechanical latency but rather merely incurs electronic switching latency and any requisite processing delays associated with re-synchronizing servo and timing information recorded on each concentric track and used for track following servo control.
Servo information is typically pre-written on disk drive media surfaces during the manufacturing process to accurately place the servo information that defines the radial position of each track thereon. Though the servo information is carefully and precisely placed on the multiple disk surfaces during the manufacturing process, mechanical and environmental conditions may change slightly over time. Thus, as a disk drive controller switches from one head to another, some delay is incurred in tuning the precise position of the next head based on the servo information recorded on its corresponding track position.
Ever increasing demands for storage capacity have led disk drive manufacturers to seek ever higher storage densities. Storage density is typically measured both linearly and radially. Linear density is measured as bits per inch ("BPI") in the longitudinal direction of a recorded track (i.e., in the direction in which the head flies over the rotating disk media). Radial density is measured in the radial direction as tracks per inch ("TPI"). A real density is a common measurement of the total storage density of a disk drive and is determined as the product of linear density (BPI) and radial density (TPI).
Numerous well-known techniques have been applied to increase in the linear density recorded around the circumference of each concentric track. Some such techniques involve simple encoding algorithms to increase the linear density while maintaining high reliability. In so-called longitudinal recording, magnetic flux changes are recorded "longitudinally" (i.e., substantially parallel to the direction of the magnetic surface rotating under the read write ahead). In "vertical" or "perpendicular" recording techniques, magnetic flux changes are recorded substantially perpendicular to the longitudinal direction of the head/media movement. Vertical or perpendicular recording provides a higher linear density of storage.
Other techniques are applied to increase the radial density (TPI). In the radial direction, the distance between the center of a recorded track and the center of an adjacent recorded track ("track pitch") tends to be larger than the width required for a successful reading. Placement of the servo information written at time of manufacture determines the center position of each track. Placing the servo information closer for each track increases the radial density. Spacing the tracks further apart than the minimum distance allows tracks to be more easily randomly re-written though the newly written (or re-written) information may be slightly displaced relative to older information previously at the same track. The magnetic flux changes representing one track are far enough from a next adjacent track that one will not interfere with reading of the other. If an adjacent track were recorded too close to another track, the sensing by the read head may receive interference sensed as noise in reading the intended track. Thus the signal to noise ratio of the data to be read may be reduced. By keeping the tracks further apart to allow for random re-writing at different times and under different conditions, the interference between tracks is reduced and the signal to noise ratio for data to be read is maintained at a higher level.
One technique generally known in the disk drive art for increasing radial density in certain storage applications is to record information in a streaming manner from one track to a next adjacent track in sequential order. Where data is so recorded sequentially with no need to randomly re-write individual tracks, the recorded data may be applied to the magnetic media at a very high radial density by densely packing the recorded information such that a next sequential track abuts or even partially overwrites an earlier recorded track. Such an operation is often referred to as "trimming" in that it trims the track pitch to nearly the minimum required for accurately sensing data. Such techniques are more readily applied in vertical or perpendicular recording but may also be applied in longitudinal recording. Key to such applications is that the data is written in a substantially continuous, sequential stream and read in a substantially continuous, sequential stream over the entire recorded area of the disk drive. In such applications the mechanical and environmental parameters that may affect track positioning and following controls will not change substantially during the continuous read or write sequence. Thus, track following servo controls may more reliably follow the center position of each concentric track and allow for closer spacing of the concentric tracks. Numerous disk storage applications may utilize such sequential writing/reading techniques such as audio/video capture or presentation and other forms of streamed data capture and presentation.
Where such overlap and trim techniques are used in recording data at a higher radial density, it is also generally known to record the concentric tracks in each of two radial directions. In other words the disk surface is written bi-directionally—a first portion of the disk is recorded on sequential tracks starting from the inner diameter (ID) of a recording surface moving toward a middle diameter (MD) and a second portion of the disk drive is recorded on sequential tracks starting from an outer diameter (OD) to the middle diameter (MD). The middle diameter (MD) is in general selected as a position where the read/write head is at a minimally skewed angle with respect to the tangent line of recording on the circular track. As the read/write head is radially positioned more inward or more outward, the geometry of the actuator arm and head mounted thereon changes a bias angle imposed between the angle of the write head and the concentric track on which it records. Typically, disk drive manufacturers try to configure the heads and actuator arms so that the bias angle is minimized at a center point in the radial travel of the head and hence averaged over the entire radial range of head travel. The middle diameter (MD) is therefore often referred to as the "zero skew" position.
Where the two directions of writing join at approximately the MD concentric track position, the overlap and trim features of the high radial density writing may render one or more tracks near MD unusable. This area is sometimes referred to as a "zipper track" or "zipper zone". As used herein, both terms refer to a zone of multiple tracks near the MD track location on each surface potentially unusable because of the overlap in bi-directional writing.
A problem arises where such bi-directional sequential writing generates such a zipper zone with multiple surfaces and associated multiple read/write heads. Track following servo mechanisms associated with a read/write head may be used to avoid the zipper zone on any surface of the disk drive. If the read/write head were allowed to enter the zipper zone, overlapped writing may render servo information useless or unreadable and hence lose synchronization for track following servo mechanisms. Therefore, control mechanisms of such a disk drive utilizing bi-directional high radial density writing carefully avoid the zipper zone on each disk surface.
However, when it is desired to switch from one head to another head in a multiple surface disk drive, misalignment of track positioning between multiple read/write heads may cause a head switch operation to switch to a second read/write head that is presently physically positioned within the zipper zone of its corresponding disk surface. In other words, though a first head may be outside its corresponding zipper zone and the track following servo controls properly functioning, the electronic switch to the second head could occur while the second head (misaligned relative to the first head) is positioned within the zipper zone of its corresponding disk surface. The two surfaces may be slightly misaligned with respect to one another due to mechanical or environmental condition changes over time in the disk drive. When such an event occurs, track following servo mechanisms may lose synchronization because the second read/write head attempts to use servo information that has been improperly overwritten or is otherwise unreadable due to its location within the zipper zone. Recovery from such a track following servo error can be a time consuming event in disk drive control and hence can diminish disk drive performance.
It is evident from the above discussion that improved head switching techniques and structures are needed where a disk drive uses bi-directional, high radial density track writing techniques that generate an unusable zipper track or a zipper zone on each of multiple disk surfaces.

Methods and structure for improved disk head switching to avoid zipper zones


The present invention is directed to components of fiber-reinforced plastics which can also be used as load-bearing components in mechanical and automotive engineering. A construction for such components is created that can be used flexibly and enables a defined design of the components. A method is created for this purpose that makes it possible to design and produce such load-bearing components to specific requirements. The method can be automatable and can make highly replicable results possible. The components thus produced of a fiber-reinforced plastic can have low weight with high strength properties and can be economical to produce.

1. Field of the Invention
The invention relates to a component comprising fiber-reinforced plastic. The invention also relates to a method for producing a component, such as a bearer or a wheel rim, wound from fiber-reinforced plastic.
2. Background Information
Fiber-reinforced plastics are increasingly used to produce components of lightweight construction. Given the progress made in developing materials in the field of plastics and fiber materials and given the low weight of the components, these components are used above all in automotive engineering for making body parts and in railroad cars for constructing passenger compartments, but are also used in aircraft construction. Depending on the type of component, laminating techniques, injection molding processes (resin transfer molding) or fiber winding processes are used to produce the components.
The fiber winding process was one of the first production methods developed for processing composites. The advantage of this method is that the fibers are wound onto a mold core in a continuous process. In it, the fibers are often saturated with a resin and wet-impregnated in the same operation. The fiber winding process is distinguished by a high quality of lamination and high precision in terms of the fiber resin content and in the fiber orientation, with at the same time a high degree of automation and great economy. The fiber winding process is used to produce not only special components, such as cover caps for rotors and the like, but also to produce cover layers, which in the case of passenger compartments are wound around a large, rectangular, hollow hard foam core.
For producing load-bearing components, such as bearers in mechanical and automotive engineering, despite the familiar advantages of composites, conventional materials such as steel, aluminum or titanium are still primarily used. These materials are cast, pressed into molds, or machined out of solid blocks. Such components made of thermoplastics are also known, but once again these are either cast or pressed into molds.
The known materials for producing load-bearing components all have either high weight or are complicated and expensive to produce and process. The use of plastic composite materials in producing vehicles of lightweight construction has not yet produced the desired results. Especially in terms of crash performance, the known plastic constructions produce only inadequate results, and therefore for crash-related load-bearing components they are generally supplemented with comparatively heavy metal constructions.

Component consisting of a fiber-reinforced synthetic material and a method for producing same


This invention relates to dictation systems that utilize cordless telephones. The cordless telephone generates audio that is received by a dictation system. The handset of the cordless telephone has a record control switch and a review/play switch thereon that control the sending and receiving of audio signals to and from the dictation system. A PBX can be connected to the base and with the dictation system so that the individual using the cordless phone is able to perform dictation activities with a plurality of dictation systems.

There are different types of dictation systems commercially available, including desk top dictating machines, relatively large central dictation systems and dictation systems that can be utilized in a small office environment. The instant invention can have use in any of these areas, but it is concerned primarily with central dictation systems that are used in locations such as hospitals, large law offices, large corporations and the like.
In a central dictation system, voice data is stored in a central memory and can be retrieved by a transcriptionist at any time without the need of transferring a medium such as a tape. Another advantage is that earlier dictated audio can be transcribed while dictation is taking place. In central dictation systems, the dictator can use a telephone that emits DTMF signals to control the functioning of the dictation system. Such telephones are well known and have been described in various patents, see for example, U.S. Pat. No. 4,969,136.
Although such central dictation systems work well, one drawback of contemporary systems is that they require a corded telephone that is stationed at a given location, thereby requiring the dictator to be at that location in order to create a message. Clearly, it would be advantageous if one could dictate a message to or obtain information from a central dictation system without being limited to a specific location or locations. In addition, it would be advantageous to give a user of the dictation equipment the ability to dictate a message or receive stored audio while being mobile. This would be particularly useful when the dictator makes reference to a large number of papers spread across a table during dictation.

Cordless telephone for use with dictation system


Systems and methods for classifying abnormalities within optical coherence tomography images of the eye are presented. One embodiment of the present invention is the classification of pigment epithelial detachments (PEDs) based on characteristics of their internal reflectivity, size and shape. The classification can be based on selected subsets of the data located within or surrounding the abnormalities. Training data can be used to generate the classification scheme and the classification can be weighted to highlight specific classes of particular clinical interest.

Detachment of the retinal pigment epithelium is characteristic of a variety of chorio-retinal diseases including age related macular degeneration (see for example Zayit-Soudry et al. "Retinal pigment epithelial detachment" Surv Ophthalmol 52(3): 227-243 2007). Various types of pigment epithelial detachments (PEDs) have been identified including serous, fibrovascular, and drusenoid among others (see for example Hartnett et al. "Classification of retinal pigment epithelial detachments associated with drusen", Graefes Arch Clin Exp Ophthalmol. 1992; 230(1):11-90. Optical coherence tomography (OCT) has provided a way to visualize, segment and classify PEDs. Previous work has categorized PEDs and drusen manually (see for example Lumbroso et al. "Morphologic Differences, According To Etiology, in Pigment Epithelial Detachments By Means of En Face Optical Coherence Tomography", Retina 31 (3): 553-558 2011, Hartnett et al. "Classification of retinal pigment epithelial detachments associated with drusen", Graefes Arch Clin Exp Ophthalmol. 1992; 230(1):11-9, Khanifar et al. "Drusen ultrastructure imaging with spectral domain optical coherence tomography in age-related macular degeneration", Ophthalmology. 2008 November; 115(11):1883-90), but this is a time consuming process requiring expert clinical input. A system and method capable of automatically segmenting and classifying PEDs would be highly desirable.
A segmentation map of RPE Elevations may provide too many drusen to be easily examined by individual B-scan inspection. An automated screening strategy, however, can give a quick assessment of the internal and surface characteristics of RPE elevations and nearby structures, which may provide a risk assessment for the development of advanced complications such as manifest fibrovascular infiltration or cellular atrophy among others.

Systems and methods for automated classification of abnormalities in optical coherence tomography images of the eye


A package for containing a coil of wire having an outer cylindrical surface extending about a coil axis, a top and an oppositely facing bottom has a base for supporting the bottom of a wire coil when the wire coil is in the package. At least one side wall extends upwardly from the base about an outer cylindrical surface of the wire coil and has an upper edge defining a top opening in the package for removing the wire. The packaging further includes a hold-down bar between the bottom of the wire coil and the base which is transverse to the axis of the wire coil, and a lifting strap having a first end, a second end and a base portion between the first and second ends and between the bottom of the wire and the base. The base portion has an opening and the hold-down bar extends through the opening.

In the welding industry, a tremendous number of robotic welding stations are each operable to draw welding wire from a package to provide a continuous supply of wire to perform successive welding operations. The advent of this mass use of electric welding wire has created a need for large packages for containing and dispensing large quantities of welding wire. A common package is a drum where looped or coiled welding wire is deposited in the drum as a wire stack, or body, of wire having a top surface with an outer cylindrical surface against the drum and an inner cylindrical surface defining a central bore. The central bore is often occupied by a cardboard cylindrical core as shown in Cooper U.S. Pat. No. 5,819,934. It is common practice for the drum to have an upper retainer ring that is used in transportation to stabilize the body of welding wire as it settles. This ring, as is shown in Cooper, remains on the top of the welding wire to push downward by its weight so the wire can be pulled from the body of wire between the core and the ring. In addition, a hold-down mechanism can be utilized to increase the downward force. As can be appreciated, large welding wire packages are heavy and require the use of lifts and other material transport devices to move the packages. As can also be appreciated, the wire packages may be moved several times before the wire is consumed. This can include several moves between the wire manufacturer and the end user and even several moves once the package reaches the end user. Therefore, it is advantageous to include a mechanism on the packaging to facilitate the use of lifting equipment to move the packaging.
Some prior art packages include handles on their outer surfaces to help grasp the container. However, handles provide little benefit for larger wire packages.
Other prior art welding wire packages include a built in packing skid or pallet to allow a fork lift to move the wire packaging. As can be appreciated, the packing skid which is heavy and bulky, and often expensive, must be disposed of once the welding wire is consumed. In view of the high volumes of welding wire used during many welding operations, especially robotic welding operations, there is a need for a wire package that is easily and economically disposable.
In order to overcome the shortcomings of packing skids, others have utilized lifting straps to lift the heavy wire packages. These lifting straps have loops on either end and the straps extend into the packaging and wrap around the base of the wire coil. The loops are utilized to attach the packaging to a lifting device. However, if only one loop is pulled, the strap can be pulled from the packaging. As can be appreciated, once the strap has been pulled from the packaging, it is difficult, if not impossible, to utilize the strap to lift the welding wire package. Further, if the strap is securely affixed to the packaging, such as by staples, it is difficult to separate the strap from the packaging after the wire is consumed. As can be appreciated, in order to recycle the packing materials, it is advantageous to be able to easily separate unlike materials, such as separating paper products of the package from the materials used to make the strap.


An architecture for creating a single image for a stack of switches. A plurality of the internetworking devices are provided in a stack configuration for interconnecting networks. Software is executed in each internetworking device such that the stack of internetworking devices appear as a single internetworking device to the interconnected networks.

1. Technical Field of the Invention
This invention is related to network switches and routers, and more specifically, to an architecture for providing a single switch image from a stack of network switches.
2. Background of the Art
None of the stacking products available in the existing market provides a single switch/router image, but only offer a facility for a single point of management. In these conventional products, each switch/router performs independently. For example, a MAC address learned in Switch A is not be propagated to Switch B in the same stack. Therefore, when Switch B receives packets destined to the MAC address already learned by Switch A, these packets are flooded by Switch B.
In those stacking products with routing functions, each switch routes packets independently, and each switch requires an independent IP address configuration per routing interface. As a result, a stack of N switches with routing functions behave externally as N independent routers. This causes inefficient use of allocated IP addresses. Additionally, packets routed through the stack may be routed more than once, and hence, experience a longer delay.
Fault tolerance is an important feature of a robust network. Conventional practices include intelligent software agents that continuously monitor redundant links. Other methods of increasing fault tolerance include redundant hardware systems, for example, stacking redundancy which ensures no single point of failure for inter-subnet routing, redundant power supplies, and port aggregation of switches, all of which address keeping critical network services active and accessible. However, these are expensive propositions in both hardware and software, and support resources, and still do not provide a fail-safe system.
What is needed is a single switch/router image for a stack of switches which causes a stack of switches to behave externally as a single switch or a single router, if routing functionality is provided. Such an architecture would provide a high level of fault tolerance without the costs associated with conventional redundant hardware and software systems.

Single switch image for a stack of switches


An object detection system includes a radar detection means (2), an image detection means (3), and a collating means (4). The collating means (4) performs a collation between an object detected by the radar detection means (2) in a present collation and an object that has been determined as being detected by the radar detection means (2) and the image detection means (3) in a previous collation (S 10, S 11), further performs a collation between an object detected by the image detection means (3) in a present collation and an object that has been determined as being detected by the radar detection means (2) and the image detection means (3) in the previous collation (S 12, S 13) when it is determined that the identical object is detected by the radar detection means (2) and the image detection means (3) in the previous collation. Then the collating means (4) determines whether the radar detection means (2) and the image detection means (3) detect the identical object based on the collations (S 14).

1. Field of Invention
The invention relates to an object detection system that detects an object using radar and images.
2. Description of Related Art
Recently an operation support system, for example, a collision avoidance control system, an adaptive cruise control system, a tracking control system and the like has been increasingly developed. The detection of an object (obstruction) such as a preceding vehicle is essential for the operation support system. An object detection system disclosed in publications JP-A-2003-84064 and JP-A-7-125567 as below includes two detection units, for example, a radar such as a laser radar, and a stereo camera that shoots an image. The object detection system performs collation between detection results of the radar and the detected image. The preceding object is detected based on the aforementioned collation results.
In the generally employed object detection system using two kinds of detection units, the respective detection results of those detection units each obtained instantaneously are collated. Deterioration in accuracy of at least one of those detection units may interfere with accurate collating operation. The detection accuracy of the aforementioned object detection system is likely to be deteriorated even if two different detection units are employed. Accordingly, such system may mistakenly detect the object or fail to detect the object.

Object detection system and object detection method