Methods for performing ring-opening cross-metathesis reactions on solid support are disclosed. Substituted cyclic compounds, libraries of the compounds, and methods of using the compounds to treat bacterial infections are also disclosed.

The need for new classes of chemical compounds for use in pharmaceutical and agricultural applications has received much attention. For example, modem synthetic chemical methods for producing regio- and stereochemically defined compounds have made possible drugs with previously unattainable activity and specificity. Nevertheless, many currently-available drugs have been designed to avoid structural complexity, due to the traditionally difficult task of economically developing compounds with dense and diverse functional arrays. Thus, new methods for the production of functionally and stereochemically diverse compounds have the potential to exploit this heretofore underexplored area.
Transition-metal mediated olefin metathesis has been recognized as an effective means for carbonxe2x80x94carbon bond formation (see, e.g., Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. (1995) 28:446; Schmalz, H. -G. Angew. Chem. Int. Ed Engl. (1995) 34(17):1833). Ring closing-metathesis has been extensively utilized for the synthesis of macrocycles, carbocycles and heterocycles (see (a) Fu, G. C. Grubbs, R. H. J. Am. Chem. Soc. (1992) 114:5426. (b) Fu, G. C. Grubbs, R. H. J Am. Chem. Soc. (1992) 114:7324. (c) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. (1993) 115:3800. (d) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. (1993) 115:9856. (e) Fujimura, O.; Fu. G. C.; Grubbs, R. H. J. Org. Chem. (1994) 59:4029. (f) Kim, S. -H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. (1994) 116:10801. (g) Miller, S. J.; Kim, S. -H.; Chen, Z. -R; Grubbs, R. H. J. Am. Chem Soc. (1995) 117:2108. (h) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. (1995) 117:5855. (i) Martin, S. F.; Liao, Y.; Rein, T. Tetrahedron Lett. (1994) 35:691. (j) Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. (1994) 35:3191. (k) Martin, S. F.; Liao, Y.; Chen. H. J.; Patzel, M.; Ramser, M. N. Tetrahedron Lett. (1994) 35:6005. (1) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. (1995) 36:1169. (m) Houri, A. F.; Xu, Z.; Cogan, D.; Hoveyda, A. J. Am. Chem. Soc. (1995) 117:2943. (n) Kim, S. -H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. (1996) 61:1073. (o) Fxc3xcrstner, A.; Langemann, K. J. Org. Chem. (1996) 61:3942. (p) Crimmins, M. T.; King, B. W. J. Org. Chem. (1996) 61:4192. (q) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. (1996) 118:6634). However, the application of intermolecular ring opening cress-metathesis (ROM) for the convergent synthesis of small organic molecules has remained relatively unexplored. Recently, solution-phase ROM of fused and bicyclic olefin systems with aliphatic alkenes yielding cyclopentane and tetrahydrofuran derivatives was reported (see (a) Schneider, M. F.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1996) 35: 411. (b) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J. Am. Chem. Soc. (1995) 117:9610. (c) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1997) 36: 257). (d) Snapper et al. J. Am. Chem. Soc. 119:1478 (1997)). For unsymmetrically substituted substrates only slight regioselectivity was generally observed. In addition, other reaction pathways, such as ring opening metathesis polymerization of the bicyclic or fused olefins competed with the desired cross-metathesis reactions.
Terminal aryl olefins have been shown to participate in selective cross-metathesis reactions utilizing a molybdenum alkylidene catalyst (see Crowe, W. E.; Zhang, Z. J. J. Am. Chem. Soc. (1993) 115:10998). The cross-metathesis of norbomene and styrene in the presence of Ru2(OAc)4 and ethyldiazoacetate has also been reported (see Noels, A. F.; Demonceau, A.; Carlier, E.; Hubert A. J.; Mxc3xa1rquez-Silva, R. -L.; Sxc3xa1nchez-Delgado, R. A. J. Chem. Soc., Chem. Commun. (1988) 783). However, an extensive utilization of aryl olefins in ROM has been absent.
Thus, previously reported ROM methods suffer from drawbacks which can render them undesirable for the synthesis of highly complex chemical compounds.
The invention relates to ring-opening cross-metathesis reactions, and to substituted cyclic compounds, libraries of compounds, and methods of preparing and using the compounds.
In one aspect, the invention provides a compound represented by the formula (Formula I):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Y is a moiety selected from the group consisting of O, S, NR5, and CR1R2Q;
Q is independently for each occurrence a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and Rxe2x80x22 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
or a first occurrence of R1 or R2, taken together with a second occurrence of R1 or R2, and the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring;
or at least one of R1, R2, Rxe2x80x21, Rxe2x80x22, or R5 is a linker group to a solid support;
or a salt thereof.
In another embodiment, the invention provides compounds represented by the formula (Formula Ia):
in which
W is CH2 or O;
Z is CHC(O)R8 or NR5;
R5 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
R6 and R7 taken together are O, or R6 is CHC(O)Rxe2x80x28 and R7 is hydrogen;
R8 and Rxe2x80x28 are each independently hydroxy, alkoxy, aryloxy, or amino; and
one of R9 and R10 is hydrogen and the other of R9 and R10 is alkyl or aryl;
or a salt thereof.
In another aspect, the invention provides compounds represented by the formula (Formula II):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Q is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and Rxe2x80x22 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
Ra and Rb are each hydrogen, or Ra and Rb taken together are O;
or a salt thereof.
In another aspect, the invention provides a method for performing a ring opening cross-metathesis reaction on a solid support. The method includes the step of reacting an immobilized bicyclic alkene with an olefin under ring opening cross-metathesis conditions, such that ring opening cross-metathesis occurs on a solid support.
In another aspect, the invention provides methods of preparing a compound of Formula I. The method includes the step of reacting a bicyclic alkene represented by the formula (Formula III):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Y is a moiety selected from the group consisting of O, S, NR5, and CR1R2Q;
Q is independently for each occurrence a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and Rxe2x80x22 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
or a first occurrence of R1 or R2, taken together with a second occurrence of R1 or R2, and the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring;
or at least one of R1, R2, Rxe2x80x21, Rxe2x80x22, or R5 is a linker group to a solid support;
or a salt thereof;
with a compound of the formula (Formula IV):
in which
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy; under ring opening cross-metathesis conditions, such that a compound of Formula I, Formula Ia, or Formula II is prepared.
In another aspect, the invention provides libraries of compounds of Formula I, Formula Ia or Formula II, and methods for preparing such libraries.
In another aspect, the invention provides pharmaceutical compositions. The pharmaceutical compositions include a compound of Formula I, Formula Ia or Formula II in a pharmaceutically acceptable vehicle.
In another aspect, the invention provides a method for treating a bacterial infection. The method includes the step of administering to a subject in need thereof an effective amount of a compound of Formula I or Formula Ia, such that the bacterial infection is treated.
The invention relates to methods for performing ring opening cross-metathesis (ROM) reactions on solid supports, and to compounds and libraries of compounds prepared by such methods.
Applying solid-phase synthesis techniques to ROM can effectively isolate the olefin immobilized on the resin, preventing unwanted olefin polymerization (see Schuster, M.; Pernerstorfer, J.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1996) 35: 1979). In addition, a solid-phase methodology can be conveniently incorporated into combinatorial library strategies (see, e.g., (a) DeWitt, S. H.; Czarnik, A. W. Acc. Chem. Res. (1996) 29:114. (b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. (1996) 29:123. (c) Ellman, J. A. Acc. Chem. Res. (1996) 29:132. (d) Gordon, E. M.; Gallop, M. A.; Patel, D. V. A.cc. Chem. Res. (1996) 29:144. (e) Lowe, G. Chem. Soc. Rev. (1995) 309), for producing an array of highly functionalized molecular scaffolds, e.g., as described infra, preferably in a diastereospecific manner. For example, it has now been found that ROM reactions performed on a solid support can have a product distribution different from the corresponding ROM reaction performed in the solution phase. As described below, ROM on solid support can have significantly improved regioselectivity and/or stereoselectivity compared to solution-phase ROM. As described in more detail below, solid-phase ROM provides access to highly substituted and functionalized molecular scaffolds, e.g., cyclopentyl, fused cyclopentyl, and tetrahydrofuranyl and fused tetrahydrofuranyl molecular platforms in a regioselective and stereoselective fashion.
Definitions
The term xe2x80x9celectron-releasing substituentxe2x80x9d is known in the art (see, e.g., J. March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd Edition, Wiley-InterScience (1991)), and, as used herein, refers to a substituent of an aryl group which has a greater tendency to release electron density to the aryl group than does a hydrogen atom. Exemplary electron releasing substituents include alkoxy (e.g., methoxy), substituted or unsubstituted amino (e.g., dimethylamino), alkylthio (e.g., methylthio), and the like.
The term xe2x80x9calkylxe2x80x9d refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
Moreover, the term alkyl as used throughout the specification and claims is intended to include both xe2x80x9cunsubstituted alkylsxe2x80x9d and xe2x80x9csubstituted alkylsxe2x80x9d, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above. An xe2x80x9caralkylxe2x80x9d moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
The term xe2x80x9carylxe2x80x9d as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as xe2x80x9caryl heterocyclesxe2x80x9d, xe2x80x9cheteroarylsxe2x80x9d or xe2x80x9cheteroaromaticsxe2x80x9d. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
Unless the number of carbons is otherwise specified, xe2x80x9clower alkylxe2x80x9d as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d have similar chain lengths. Preferred alkyl groups are lower alkyls.
The terms xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d refer to 3- to 10-membered ring structures, more preferably 4- to 7-membered rings, which ring structures include one to four heteroatoms. Heterocyclyl groups include pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, lactones, cyclic anhydrides, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
The terms xe2x80x9cpolycyclylxe2x80x9d or xe2x80x9cpolycyclic groupxe2x80x9d refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are xe2x80x9cfused ringsxe2x80x9d. Rings that are joined through non-adjacent atoms are termed xe2x80x9cbridgedxe2x80x9d rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, aralkyl, or an aromatic or heteroaromatic moiety.
The term xe2x80x9cstannyl,xe2x80x9d as used herein, refers to a group represented by the formula:
in which R11 and R12 and R13 are each independently alkyl or aryl
The term xe2x80x9csilyl,xe2x80x9d as used herein, refers to a group represented by the formula:
in which R11, R12 and R13 are each independently alkyl or aryl.
The term xe2x80x9cboronato,xe2x80x9d as used herein, refers to a group represented the formula:
in which R14 and R15 are each independently alkyl, aryl, or a salt-forming cation.
The term xe2x80x9cheteroatomxe2x80x9d as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
The term xe2x80x9clinker group,xe2x80x9d as used herein, refers to a linking or spacing moiety which can be used to covalently or non-covalently link a compound to a solid support. Linker groups suitable for use in the invention are known in the art for use in solid-phase synthesis.
The term xe2x80x9csubstantially pure,xe2x80x9d as used herein, refers to a compound which is substantially free of impurities, including (but not limited to) starting materials, side products, and the like. A compound is xe2x80x9csubstantially purexe2x80x9d if it comprises at least about 80%, more preferably 90%, still more preferably at least about 95% of the composition. If a single isomer of a compound is desired (e.g., a single diastereomer, enantiomer, or regioisomer), the compound is preferably substantially free of any undesired isomers (e.g., the unwanted enantiomer, diastereomers, or regioisomers), i.e., the desired isomer comprises at least about 80%, more preferably 90%, still more preferably at least about 95% of the weight of the isomers present in the composition.
The term xe2x80x9csubject,xe2x80x9d as used herein, refers to an animal, more preferably a warm-blooded animal, most preferably a mammal, including cattle, sheep, pigs, horses, dogs, cats, rats, mice, and humans.
The term xe2x80x9ctreating a bacterial infection,xe2x80x9d as used herein, refers to preventing an infection, preventing spread of an infection, or decreasing the extent or severity of a bacterial infection. In a preferred embodiment, the bacterial infection is cured, i.e., substantially eliminated.
It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, alkenes can include either the E- or Z- geometry, where appropriate.
I. Compounds
In one aspect, the invention provides compounds which can be represented by the formula (Formula I):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Y is a moiety selected from the group consisting of O, S, NR5, and CR1R2Q;
Q is independently for each occurrence a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and R12 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy, with the proviso that R3 and R4 are not both hydrogen;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
or a first occurrence of R1 or R2, taken together with a second occurrence of R1 or R2, and the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring;
or at least one of R1, R2, Rxe2x80x21, Rxe2x80x22, or R5 is a linker group to a solid support;
or a salt thereof.
In certain preferred embodiments, at least one of R1, R2, Rxe2x80x21, Rxe2x80x22, or R5 is a linker group to a solid support. In preferred embodiments, R3 and R4 are not the same, i.e., are different moieties. In preferred embodiments, at least one of R3 and R4 is aryl. In particularly preferred embodiments, R3 and R4 are not both hydrogen. In preferred embodiments, X is not a direct bond. In certain embodiments, X is O, while in other embodiments, X is CH2. In certain preferred embodiments, Q is a direct bond. In preferred embodiments, R5 is xe2x80x94CH2C(O)R8, in which R8 is hydroxy, alkoxy, aryloxy, or amino.
In certain preferred embodiments, if X is CH2 or O, and Y is methylene (i.e., Y is CR1R2Q and Q is a direct bond), then R3 and R4 are different. In certain preferred embodiments, if X is CH2 or O, and Y is methylene (i.e., Q is a direct bond), then R1 and R2 are different. In certain preferred embodiments, if X is a direct bond, and Y is CR1R2Q, then Q is not CR1R2. In preferred embodiments, if X is CH2 or O, and Y is NR5 or CR1R2Q, and Q is a direct bond, then at least one of R3 and R4 is aryl. In preferred embodiments, if X is O, and one of R3 and R4 is aryl, the other of R3 and R4 is not alkyl.
In particularly preferred embodiments, the compounds of the invention can be represented by the formula (Formula Ia):
in which
W is CH2 or O;
Z is CHC(O)R8 or NR5;
R5 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
R6 and R7 taken together are O, or R6 is CHC(O)Rxe2x80x28 and R7 is hydrogen; and
R8 and Rxe2x80x28 are each independently hydroxy, alkoxy, aryloxy, or amino;
or a salt thereof.
In preferred embodiments of the compounds of Formula Ia, if Z is NR5, then R6 and R7 taken together are O. In certain preferred embodiments, Z is CHC(O)R8, R6 is CHC(O)Rxe2x80x28 and R7 is hydrogen. In preferred embodiments, at least one of R5, R8 and Rxe2x80x28 is a linker to a solid support. In certain preferred embodiments, one of R9 and R10 is an aryl group which is substituted with one or more electron-releasing substituents; more preferably, one of R9 and R10 is a 4-methoxyphenyl group. In preferred embodiments, W is CH2. In certain preferred embodiments, Z is CHC(O)R8, R6 is CHC(O)Rxe2x80x28 and R7 is hydrogen.
Thus, the invention provides a wide variety of highly substituted and functionalized compounds, e.g., substituted cyclobutanes, oxetanes, xcex2-lactams, cyclopentanes, cyclohexanes, tetrahydrofurans, tetrahydropyrans, pyrrolidines, piperidines, 2-oxapiperidines, 1,3-dioxanes, tetrahydrothiophenes, and the like. For example, when X and Y in the compound of Formula I are both carbon (and Q is a direct bond), the compound is a cyclopentane derivative. In another example, when X is a direct bond in the compound of Formula I, Y is carbon (and Q is a direct bond), the compound of Formula I is a cyclobutane derivative. In yet another example, when X is NR5, and Y is carbon (and Q is a direct bond) the compound is a substituted pyrrolidine.
Compounds such as substituted cyclopentanes, tetrahydrofurans, and pyrrolidines are common in nature, and are also present in a variety of synthetic compounds including pharmaceuticals and agrochemicals. For example, prostaglandins and other prostanoids are substituted cyclopentane or cyclopentene derivatives. Muscarine, a naturally-occurring alkaloid, is a cholinomimetic which includes the tetrahydrofuran structure. Nicotine is a substituted pyrrolidine which has been used as an agricultural insecticide. The invention thus provides analogs or derivatives of these and other compounds, and methods of preparing such compounds, as described herein.
Moreover, the compounds of the invention can have a variety of closely spaced functionalities and may serve as interesting molecular scaffolds. Such molecular scaffolds can be used to present pharmacophores to certain receptors. For example, the compounds of the invention, having suitable functional groups, may have biological activity such as CNS activity, activity at steroid receptors, antiinflammatory activity, protein kinase C inhibitory activity, antifungal or antibacterial activity, opiate receptor activity, and the like. For example, as described in Example 6, infra, certain of the compounds of the invention exhibit moderate antibacterial activity in in vitro screening assays.
In another embodiment, the invention provides compounds of Formula II:
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Q is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and Rxe2x80x22 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
Ra and Rb are each hydrogen, or Ra and Rb taken together are O;
or a salt thereof.
In preferred embodiments of the compound of Formula II, X is O or CH2. In certain preferred embodiments of the compound of Formula II, R3 is hydrogen. In certain preferred embodiments of the compound of Formula II, R4 is aryl, and more preferably, aryl having at least one electron-releasing substituent. In certain preferred embodiments, Ra and Rb taken together are O. It will be appreciated by the skilled artisan that compounds in which Ra and Rb taken together are O can be converted to the corresponding compound in which Ra and Rb are each H by reduction, e.g., by treatment with diborane, as is known in the art.
In preferred embodiments, the compound of Formula I, Ia or II is substantially pure, i.e., the compound is at least 80%, 90% or 95% pure. Compounds which are not substantially pure can be purified by conventional methods, including the methods described infra.
It has now been found that the compounds of the invention have anti-bacterial activity. For example, as described in Example 6, infra, certain compounds of the invention have activity against gram-positive bacteria. Accordingly, in a preferred embodiment, a compound of the invention has anti-bacterial activity. Preferred compounds include compounds of Formula I in which X is CH2. In certain preferred embodiments, R1 is H. In some preferred embodiments, R3 is H. In certain preferred embodiments, Y is carbon, e.g., xe2x80x94CH(C(O)NR9R10)xe2x80x94, in which R9 and R10 are each independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl; or R9 and R10, taken together with the nitrogen to which they are attached, form a heterocyclic ring.
II. Methods
In another aspect, the invention provides methods for performing ring-opening cross-metathesis reactions. In one embodiment, the method includes the steps of reacting an immobilized bicyclic alkene with a terminal olefin under ring opening cross-metathesis conditions, such that ring opening cross-metathesis occurs on a solid support. In a preferred embodiment, the terminal olefin is a terminal aryl olefin.
In another embodiment, the invention provides a method for performing ring opening cross-metathesis reactions of a bicyclic alkene with a terminal aryl olefin. The method includes the step of reacting a bicyclic alkene with a terminal aryl olefin under ring opening cross-metathesis conditions, such that ring opening cross-metathesis occurs.
The invention also provides a method for preparing a compound of Formula I. In one embodiment, the method includes the steps of reacting a compound represented by the formula (Formula III):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Y is a moiety selected from the group consisting of O, S, NR5, and CR1R2Q;
Q is independently for each occurrence a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and Rxe2x80x22 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
or a first occurrence of R1 or R2, taken together with a second occurrence of R1 or R2, and the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring;
or at least one of R1, R2, Rxe2x80x21, Rxe2x80x22, or R5 is a linker group to a solid support;
or a salt thereof;
with a compound of the formula (Formula IV):
in which
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy;
under ring opening cross-metathesis conditions, such that a compound of Formula I is prepared.
In preferred embodiments of the compound of Formula III, at least one of R1, R2, Rxe2x80x21, Rxe2x80x22, or R5 is a linker group for covalently linking the compound of Formula I and/or Formula II to a solid support. Exemplary linker groups are described infra. In certain preferred embodiments, X is O or CRxe2x80x21Rxe2x80x22. In certain preferred embodiments, if Y is NR5, then R1 and R2 taken together are O.
In certain preferred embodiments of Formula III, in at least one occurrence R5 is xe2x80x94C(O)NR14R15, in which R14 and R15 are each independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl; or R14 and R15, taken together with the nitrogen to which they are attached, form a heterocyclic ring. In preferred embodiments, one of R14 and R15 is hydrogen, i.e., R1 is a monosubstituted carboxamide. In this embodiment, R1 can comprise a linking moiety. In other embodiments, R14 and R15, taken together with the nitrogen to which they are attached, form a 1,4-piperazinyl moiety, which, in certain embodiments, can be substituted, e.g., with a linker moiety.
In preferred embodiments of the compound of Formula IV (hereinafter referred to as an xe2x80x9colefinxe2x80x9d), if R4 is aryl, then R3 is hydrogen. In particularly preferred embodiments, R4 is substituted aryl, in which the aryl group has at least one electron-releasing group.
In certain embodiments, the methods of the invention include the further step of purifying the compound of Formula I and/or Formula II (e.g., by washing the solid support upon which the compound is immobilized). In certain embodiments, the method includes the further step of cleaving the compound of Formula I and/or Formula II from the solid support. In certain embodiments, the method includes the step of purifying the compound (or compounds) produced in the ring opening cross-metathesis reactions. In certain embodiments, the compound or compounds of Formula I and/or Formula II can be further reacted, e.g., to produce derivatives and analogs of compounds of Formula I and/or Formula II.
The invention also provides methods for preparing a compound of Formula II. The method includes the steps of reacting a compound represented by the formula (Formula V):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CRxe2x80x21Rxe2x80x22Q;
Q is a direct bond or a moiety selected from the group consisting of O, S, NR5, and CR1R2;
P is hydrogen or a protecting group;
R1 and R2 are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
Rxe2x80x21 and Rxe2x80x22 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R1 and R2 taken together are O or S;
R5 is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
Ra and Rb are each hydrogen, or Ra and Rb taken together are O;
or a salt thereof;
with a compound represented by the formula (Formula IV):
in which
R3 and R4 are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy;
under ring opening cross-metathesis conditions, such that a cross-metathesis product is prepared; and cyclizing the cross-metathesis product, such that a compound of Formula II is prepared.
In preferred embodiments, the step of cyclizing the cross-metathesis product includes exposing the cross-metathesis product to acidic conditions, such that ring closure occurs. In preferred embodiments, the step of cyclizing the cross-metathesis product is performed without purification of the cross-metathesis product. In preferred embodiments, P is hydrogen or a protecting group which can be removed under the conditions of the step of cyclizing the cross-metathesis product, e.g., P can be removed under acidic conditions. Amine protecting groups which can be removed under acidic conditions are well known (e.g., the t-butyloxycarbonyl (BOC) group). For a discussion of suitable protecting groups, see, e.g., Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd ed., Wiley, 1991). In the compounds of Formula V, the protecting group P can also be a solid support or a linker to a solid support (see, e.g., Examples 5 and 6, infra, in which cleavage from the solid support occurs under acidic conditions, with concomitant cyclization to compounds of Formula II).
The invention also provides methods for preparing compounds of Formula Ia. In one embodiment, the method includes the steps of reacting a compound represented by the formula (Formula VI):
in which
W is CH2 or O;
Z is CHC(O)R8 or NR5;
R5 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
R6 and R7 taken together are O, or R6 is CHC(O)Rxe2x80x28 and R7 is hydrogen;
R8 and Rxe2x80x28 are each independently hydroxy, alkoxy, aryloxy, or amino; and
one of R9 and R10 is hydrogen and the other of R9 and R10 is alkyl or aryl;
or a salt thereof;
with a compound represented by the formula (Formula VII)
under ring opening cross-metathesis conditions, such that a compound of Formula Ia is prepared. In preferred embodiments, the bicyclic alkene is immobilized on a solid support. In particularly preferred embodiments, the ring opening cross-metathesis reaction is a regioselective reaction.
In preferred embodiments of the methods of the invention, the ring-opening cross-metathesis conditions include a catalyst, preferably a molybdenum or ruthenium catalyst, such as are described herein.
The methods of the invention provide several advantages over ring opening cross-metathesis reactions previously reported. For example, when the bicyclic alkene of Formula III is immobilized on a solid support, the undesired polymerization of the bicyclic alkene, which may be a significant side reaction when ROM reactions are performed in the solution phase, can be minimized. Furthermore, the ROM reactions of the invention proceed cleanly, in good yield, and are the products can be easily and quickly isolated and purified, often by simply filtering the solid support, washing to remove impurities, and cleaving the product from the solid support.
The present method can also provide stereo- and regioselective ROM reactions. For example, as described in Example 3, infra, the ROM reactions of the invention can be more regioselective than the corresponding ROM performed in the solution-phase. Thus, higher yields of a desired product can be obtained, with less wasted side product (e.g., undesired stereo- or regioisomers), thereby providing a more economical synthesis. Moreover, by appropriate choice of the substitutents of the bicyclic alkene and the olefin, the product ratio of the ROM reaction can be influenced to produce either one of two products in preference to the other. Thus, in a preferred embodiment, the ROM reactions of the invention are regioselective, i.e., produce one product in preference to a regioisomer of that product. In preferred embodiments, the mole ratio of regioisomers is at least about 1.5:1, more preferably at least about 2:1, and still more preferably at least about 3:1.
Similarly, judicious selection of substituents can provide compounds having pre-selected stereochemistry. For example, the rigid bicyclic framework of a bicyclic alkene can be chosen such that the ring-opened product bears an array of functional groups in predictable stereochemical relation. For example, when a compound of Formula III is employed in the methods of the invention, the resulting cyclic compound of Formula I will have an R2 substituent (if any) on the ring which is cis relative to the vinyl groups bearing R3 and R4. Moreover, the use of chiral reactants or chiral solid supports can promote the predominant formation of one enantiomer of two possible enantiomeric products.
Reactants
In general, the solid-phase ROM reactions of the invention involve reaction of a bicyclic alkene with an olefin. In certain embodiments, bicyclic alkenes which can be used in the methods of the invention can be represented by Formula III, Formula V, or Formula VI. A variety of bicyclic alkenes having the general structure of Formula III, Formula V, or Formula VI are known in the art, and many bicyclic alkenes can be purchased commercially.
Bicyclic alkenes suitable for use in the methods of the invention will be sufficiently reactive to undergo a ROM reaction with an alkene (usually in the presence of a catalyst). Without wishing to be bound by theory, it is believed that ring strain increases the rate of ROM reaction of a bicyclic alkene, i.e., relief of ring strain provides a driving force for ROM. Accordingly, highly strained bicyclic alkenes are preferred. Bicyclic alkenes contemplated for use in the methods of the invention include compounds having a [2.2.1], [2.2.2] or [3.2.0] ring system. Bicyclic alkenes having a [2.2.1] ring system are preferred. Illustrative examples of bicyclic alkenes include substituted or unsubstituted compounds norbornene, norbornadiene, 7-oxanorbornene, 7-oxanorbornadiene, and the like.
In preferred embodiments, the bicyclic alkene of Formula III, Formula V, or Formula VI is immobilized on a solid support. Such immobilization can be covalent, or can be due to ionic, hydrophobic, hydrophilic, or other interactions between the compound and the support. Linkers can be used to provide for convenient attachment to, and release from, the solid support (see infra). Thus, the bicyclic alkene preferably includes at least one functional group which can be used to immobilize the bicyclic alkene on the solid support.
An olefin which reacts with a bicyclic alkene in a ROM reaction preferably has the structure shown in Formula IV. In preferred embodiments, if either of R3 and R4 is aryl, the olefin is monosubstituted (i.e., the remaining substituents of the olefinic bond are hydrogen). Thus, terminal aryl olfins are preferred for reaction with a bicyclic alkene. If neither of R3 and R4 is aryl, the olefin can be a 1,2-disubstituted olefin (having either the E- or Z-configuration at the double bond). In certain embodiments, at least one of R3 and R4 can comprise a functional group (e.g., a linker moiety) which can be used to immobilize the olefin on a slid support.
It has been found that terminal aryl olefins having at least one electron-releasing substitutent can react to provide products with high regioselectivity (See, e.g., Example 3, infra). Accordingly, in certain embodiments, terminal aryl olefins having at least one electron-releasing substituent are preferred. However, in certain embodiments, the use of an aryl olefin having an electron-releasing substituent can result in the undesired regioisomeric product; accordingly, in certain embodiments, the aryl group does not include an electron-releasing substituent. The skilled artisan will be able to select appropriate substituents of the olefin (e.g., substituted aryl groups) for a particular product using no more than routine experimentation.
Catalysts
Catalysts useful in the methods of the invention include catalysts known in the art to be useful for ring opening or ring-closing cross-metathesis or polymerization reactions. Examples of such catalysts include the catalysts described in U.S. Pat. No. 5,342,909 and 4,945,144, both to Grubbs et al. Other catalysts may find use in the methods of the invention. In general, such catalyst are alkylidene complexes of transition metals such as molybdenum or ruthenium. For examples of catalysts useful in olefin metathesis reactions, see, e.g., thee references cited in notes 2 and 8, infra. A catalyst will generally be selected to have suitable activity with a selected bicyclic alkene and olefin. For example, certain catalysts can be sensitive to particular functional groups of the bicyclic alkene or olefin, which can deactivate a catalyst. In such a case, another catalyst should be chosen. In light of the teachings herein, the choice of an appropriate catalyst can be made by the skilled artisan using no more than routine experimentation.
In certain embodiments, the catalyst can be prepared in an immobilized form (i.e., immobilized on an inert solid support) for ease of handling and recycling (see, e.g, Nyugen et al, J. Orgmet. Chem. 497:195-200 (1995)).
Linkers
Linkers useful for immobilizing compounds on a solid support are well known in the art and include, e.g., diamino linkers, phenylene moieties, and the like. A particularly preferred linker is the linker described in Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589. This linker is easily synthesized, stable under a variety of reaction conditions, and readily cleaved to release the product from the solid support.
It will be understood that the linker can be selected to have a length which permits facile reaction with a substrate compound immobilized on a solid support. For example, the linker should be long enough to avoid steric encumbrance of the immobilized compound by the solid support. The linker can be selected to be cleavable under a variety of conditions (e.g., hydrolytic, nucleophilic, electrolytic, oxidative, photolytic, and the like), if desired, as is known in the art. The skilled artisan will appreciate that the choice of linker, in combination with the choice of solid support, can influence factors such as reaction time, completeness of reaction, releasability of the reaction products, and the like. Thus, the linker and solid support will in general be selected to permit ready immobilization, reaction, isolation, and purification of the compounds of the invention.
Solid supports
Solid supports suitable for use in solid phase synthesis are known in the art (for examples, see, e.g., M. Bodansky xe2x80x9cPrinciples of Peptide Synthesisxe2x80x9d, 2nd edition, Springer-Verlag, Berlin (1993); Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; and references cited therein). Many such art-recognized solid supports are useful in the methods of the invention. For example, solid supports suitable for use in the present invention include suitably modified forms of: silica (e.g., particles such as silica gel), silicon (e.g., wafers or chips), glass (e.g., a glass plate or controlled pore glass beads), polystyrene, polyacrylamide, Tenta-Gel, Wang resin, Rapp resin, Merrifield resin, Rink resin, and the like.
Reaction Conditions
The reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the process of the invention.
In general, it is desirable that reactions are run using mild conditions that will not adversely affect the bicyclic alkene, the olefin, the catalyst, the intermediates, the resin, the linker or the products. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants, resin, and catalyst. The reactions will usually be run at temperatures in the range of xe2x88x9278xc2x0 C. to 100xc2x0 C., more preferably in the range xe2x88x9220xc2x0 C. to 50xc2x0 C. and still more preferably in the range xe2x88x9220xc2x0 C. to 25xc2x0 C.
In general, the reactions according to the invention will be performed in a liquid medium, e.g., in a suspension of a solid support in a liquid medium. The reactions may be run in an inert solvent, preferably one in which the reaction ingredients, optionally including the polymeric support, are substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents. The reactions can be conducted under anhydrous conditions and in certain embodiments it is preferable to perform the reactions under an inert atmosphere of a gas such as nitrogen or argon.
The progress of the metathesis reactions can be monitored by techniques known to one of ordinary skill in the art. For example, aliquots of the reaction mixture can be taken at intervals and the aliquots tested, e.g., by cleavage of compounds from the solid support followed by spectroscopic analysis of the crude reaction mixture. Alternatively, the reaction can be monitored by chromatographic techniques such as thin-layer chromatography (TLC) or HPLC.
In certain embodiments, the methods for preparing compounds include the further step of purifying the compounds. Purity of the reaction products can be determined according to known techniques. If the products are impure, they can be purified according to a variety of methods known in the art. For example, compounds immobilized on a solid support can be separated from some impurities by simple filtration and washing of the solid support to remove soluble impurities. Compounds which are not immobilized on solid supports can be purified by methods including crystallization (where the compound is crystalline), trituration, distillation, and chromatographic techniques such as TLC and HPLC (analytical or preparative scale), flash chromatography, and the like. The selection of methods for purifying compounds will be routine for the ordinarily skilled artisan.
In preferred embodiments, the purity of a compound produced according to the methods of the invention is at least about 50%, more preferably at least about 70%, still more preferably at least about 90%, and most preferably at least about 95%.
In another aspect, the invention provides methods for treating bacterial infection. In general, the method comprises administering to a subject in need thereof an effective amount of a compound of the invention, such that the bacterial infection is treated. The compound of the invention can be, e.g., a compound of Formula I or Formula II, and can optionally be administered in a pharmaceutically acceptable vehicle. Bacterial infections which can be treated according to the methods of the invention include (but are not limited to) infections due to gram-positive bacteria such as Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), or vancomycin-resistant Enterococcus faceium (VREF). It will be understood that more than one compound of the invention can be employed to treat a bacterial infection; such multi-drug therapy can be useful to provide a broader spectrum of action against bacteria or to prevent the development of drug-resistant bacterial strains.
As is described in more detail below, a compound of the invention can be administered to a subject topically, e.g., to treat a localized bacterial infection, or systemically, e.g., to treat a systemic bacterial infection. The compound of the invention is preferably administered such that the bacterial infection is cured.
In certain preferred embodiments, the compound is a compound of Formula I in which X is CH2. In certain preferred embodiments, R1 is H. In some preferred embodiments, R3 is H. In certain preferred embodiments, Y is carbon, e.g., xe2x80x94CH(C(O)NRxe2x80x214Rxe2x80x215)xe2x80x94, in which Rxe2x80x214 and Rxe2x80x215 are each independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl; or Rxe2x80x214 and Rxe2x80x215, taken together with the nitrogen to which they are attached, form a heterocyclic ring.
III. Libraries
In another aspect, the invention provides libraries of compounds of Formula I, Formula Ia or Formula II, and methods of preparing such libraries.
The synthesis of combinatorial libraries is well known in the art and has been reviewed (see, e.g., E. M. Gordon et al., J. Med. Chem. 37:1385-1401 (1994)). Thus, the subject invention contemplates methods for synthesis of combinatorial libraries of compounds of Formula I or Formula II. Such libraries can be synthesized according to a variety of methods. For example, a xe2x80x9csplit-poolxe2x80x9d strategy can be implemented in the following way: beads of a functionalized polymeric support are placed in a plurality of reaction vessels. To each aliquot of beads is added a solution of a different bicyclic alkene, and the reactions proceed to yield a plurality of immobilized bicyclic alkenes. The aliquots of derivatized beads are then washed, xe2x80x9cpooledxe2x80x9d (i.e., recombined), and the pool of beads is again divided, with each aliquot being placed in a separate reaction vessel. To each reaction vessel is added a solution of a different olefin in solution (e.g., a terminal aryl olefin) and a catalyst, and reaction occurs to yield a plurality of reaction vessels each containing a plurality of compounds of Formula I immobilized on solid support. The library of immobilized compounds can then be washed to remove impurities. In certain embodiments, the compound of Formula I can further be treated (e.g., by cleavage, if desired, and cyclization) to yield a compound of Formula II.
In another illustrative method of combinatorial synthesis, a xe2x80x9cdiversomer libraryxe2x80x9d is created by the method of Hobbs, DeWitt et al. (Proc. Natl. Acad. Sci. U.S.A. 90:6909 (1993)). Aliquots of functionalized polymeric support beads are placed in an array of reaction vessels, and one of a plurality of bicyclic alkenes is introduced into each vessel. After reaction, the beads are washed to yield an array of immobilized bicyclic alkenes. Each vessel in the array is then reacted with one of a plurality of olefins, in the presence of a catalyst. After reaction, purification and workup yields a soluble library of substituted compounds of Formula I and/or Formula II.
Other synthesis methods, including the xe2x80x9ctea-bagxe2x80x9d technique of Houghten (see, e.g., Houghten et al., Nature 354:84-86 (1991)) can also be used to synthesize libraries of compounds according to the subject invention.
Combinatorial libraries can be screened to determine whether any members of the library have a desired activity, and, if so, to identify the active species. Methods of screening combinatorial libraries have been described (see, e.g., Gordon et al., J Med. Chem., op. cit.). Soluble compound libraries can be screened by affinity chromatography with an appropriate receptor to isolate ligands for the receptor, followed by identification of the isolated ligands by conventional techniques (e.g., mass spectrometry, NMR, and the like). Immobilized compounds can be screened by contacting the compounds with a soluble receptor; preferably, the soluble receptor is conjugated to a label (e.g., fluorophores, colorimetric enzymes, radioisotopes, luminescent compounds, and the like) that can be detected to indicate ligand binding. Alternatively, immobilized compounds can be selectively released and allowed to diffuse through a membrane to interact with a receptor. Exemplary assays useful for screening the libraries of the invention are known in the art (see, e.g., E. M. Gordon et al., J. Med. Chem. 37:1385-1401 (1994)).
Combinatorial libraries of compounds can also be synthesized with xe2x80x9ctagsxe2x80x9d to encode the identity of each member of the library (see, e.g., W. C. Still et al., U.S. Pat. No. 5,565,324 and PCT Publication No. WO 94/08051). In general, this method features the use of inert, but readily detectable, tags, that are attached to the solid support or to the compounds. When an active compound is detected (e.g., by one of the techniques described above), the identity of the compound is determined by identification of the unique accompanying tag. This tagging method permits the synthesis of large libraries of compounds which can be identified at very low levels.
In preferred embodiments, the libraries of compounds of the invention contain at least 30 compounds, more preferably at least 100 compounds, and still more preferably at least 500 compounds. In preferred embodiments, the libraries of compounds of the invention contain fewer than 109 compounds, more preferably fewer than 108 compounds, and still more preferably fewer than 107 compounds.
A library of compounds is preferably substantially pure, i.e., substantially free of compounds other than the intended products, e.g., members of the library. In preferred embodiments, the purity of a library produced according to the methods of the invention is at least about 50%, more preferably at least about 70%, still more preferably at least about 90%, and most preferably at least about 95%.
The libraries of the invention can be prepared according to the methods of the invention, wherein at least one of the bicyclic alkene and the olefin is provided as a variegated population. In a preferred embodiment, the methods for preparing libraries are performed on a solid support (i.e., at least one of the bicyclic alkene or the olefin is immobilized on a solid support). The term xe2x80x9cvariegated populationxe2x80x9d, as used herein, refers to a population including at least two different chemical entities, e.g., of different chemical structure. For example, a xe2x80x9cvariegated populationxe2x80x9d of bicyclic alkenes would comprise at least two different bicyclic alkenes. Similarly, a variegated population of olefins comprises at least two different olefins. Use of a variegated population of linkers can produce a variety of compounds upon cleavage of the linkers (see, e.g., Example 6, infra). Thus, the methods of the invention also can include the further step of providing a variegated population of linkers.
Libraries of the invention are useful, e.g., for drug discovery. For example, a library of the invention can be screened (e.g., according to the methods described herein) to determine whether the library includes compounds having a pre-selected activity. Thus, for example, a library can be screened to determine whether compounds of the library have anti-bacterial activity or any other activity which can be detected in vitro or in vivo, e.g., anti-inflammatory activity, enzyme inhibitory activity, and the like.
IV Pharmaceutical Compositions
In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam.
The phrase xe2x80x9ctherapeutically-effective amountxe2x80x9d as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect by treating (i.e., preventing or ameliorating) a bacterial infection in a subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject peptidomimetic agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer""s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
As set out above, certain embodiments of the present compounds can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) xe2x80x9cPharmaceutical Saltsxe2x80x9d, J. Pharm. Sci. 66:1-19).
In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, a any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agarxe2x80x94agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the peptidomimetic in the proper medium. Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral or topical administration is preferred.
The phrases xe2x80x9cparenteral administrationxe2x80x9d and xe2x80x9cadministered parenterallyxe2x80x9d as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases xe2x80x9csystemic administration,xe2x80x9d xe2x80x9cadministered systemically,xe2x80x9d xe2x80x9cperipheral administrationxe2x80x9d and xe2x80x9cadministered peripherallyxe2x80x9d as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient""s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the derivative (e.g., ester, salt or amide) thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, doses of the compounds of this invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 0.1 to about 40 mg per kg per day.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
Exemplification
Nuclear magnetic resonance (NMR) spectra were recorded using a 300 MHz Varian Unity Fourier transform NMR spectrometer. Low resolution mass spectra (LRMS) were obtained by direct injection of samples in methanol into a single quadrapole mass spectrometer (Finnigan SSQ 7000) equipped with an atmospheric pressure ionization module (APCI-MS). High resolution mass spectroscopy (HRMS) was performed by M-Scan, West Chester, Pa. Elemental analyses were performed by Atlantic Microlabs, Inc., Norcross, Ga. High pressure liquid chromatography (HPLC) was performed on a Hewlett-Packard 1090 instrument with a C18 column (4.6 mmxc3x9725 cm) and a diode array detector (peakwidth: 0.53 min, sampling interval: 0.32 min, spectrum from 200-350 nm). A flow rate of 1 mL/min, oven temperature of 40xc2x0 C. and an injector volume of 4 xcexcL were used. The eluent was a mixture of water and acentonitrile both containing 0.05% trifluoroacetic acid (TFA). HPLC samples were prepared in water/acetonitrile (1:1). A small amount of methanol was sometimes added to increase solubility. The following two methods were used:
All metathesis reactions were conducted under an argon atmosphere in dichloromethane (Aldrich Chem. Co.) stored under nitrogen in SurelSeal(trademark) bottles. All reagents obtained from commercial sources were used without further purification, unless otherwise indicated. Bis(tricyclohexylphosphine)benzylidine ruthenium dichloride, 1, was purchased from Strem Chemicals, Inc. Wang Resin (1% divinylbenzene cross-linked; 0.85-1.01 mmol/g; 100-200 mesh) was purchased from Advanced ChemTech, Louisville, Ky. The resin was saturated with reaction solvent prior to use. For metathesis reactions the resin was saturated with dichloromethane in an inert atmosphere prior to the addition of the other reaction materials.


A continuously variable transmission includes: first to third power transmission components; a rolling component; a support shaft for the rolling component; a first guide member that includes a first guide portion for guiding a first protrusion portion of the inserted support shaft; a gear shift member that includes a gear change portion; a first actuator which tilts each rolling component by moving each second protrusion portion along the gear change portion with rotation of the gear shift member at a time an input-output gear ratio is changed; a second guide member that includes a second guide portion for guiding a second protrusion portion of the inserted support shaft; and a second actuator which prohibits rotation of the second guide member during reverse rotation of the first and second power transmission components and allows rotation of the second guide member during normal rotation of the first and second power transmission components.

1. Field of the Invention
The present invention relates to a traction drive type continuously variable transmission that continuously changes an input-output gear ratio.
2. Description of the Related Art
Conventionally, for example, a ball planetary type continuously variable transmission disclosed in Japanese National Publication of International Patent Application No. 2012-506001 and Japanese Patent Application Laid-open No. 2012-225390 is known. The continuously variable transmission includes three power transmission components (two disks or two rings and a sun roller) which have a common rotation axis, rolling components (planet balls) which are radially disposed with respect to the rotation axis and are sandwiched by the three power transmission components, and holding components (carriers) which respectively hold the planet balls in a tiltable and spinnable manner through both ends of a support shaft. Each holding component includes two disk-shaped plates of which the center axes match the rotation axis. In the continuously variable transmission disclosed in Japanese National Publication of International Patent Application No. 2012-506001, one plate (a rotation plate) is rotated with respect to the other plate (a fixed plate) about the rotation axis, so that each rolling component is tilted along with each support shaft. For this reason, the fixed plate is provided with a guide portion which guides one end of the support shaft in the radial direction of the plate. Further, the rotation plate is provided with a gear change portion (that is, the gear change portion which tilts the guide portion of the fixed plate in the circumferential direction of the plate) of which the longitudinal direction is tilted in the circumferential direction of the plate with respect to the radial direction of the plate. The other end of the support shaft is inserted into the gear change portion and moves along the gear change portion with the rotation of the rotation plate. Further, in the continuously variable transmission disclosed in Japanese Patent Application Laid-open No. 2012-225390, a different fixed plate is provided between the rotation plate and each rolling component so as not to be rotatable as in the fixed plate. The different fixed plate is provided with a guide portion which guides the other end of the support shaft in the radial direction.
In such a continuously variable transmission, a fixed plate is provided between the rotation plate and each rolling component. Therefore, a skew generated by a deviation of the rotation axes of the rolling components is not generated because of the two fixed plates, and a gear ratio cannot be assured during normal rotation. In that case, it can be considered that the fixed plate provided between the rotation plate and each rolling component is made rotatable to generate a skew for assuring the gear ratio during the normal rotation. However, if the fixed plate is made rotatable, when the rotation directions of the first and second power transmission components are reversed, the forces applied therebetween do not match each other. For this reason, a divergence in skew angle occurs. As a result, there is a possibility that the rotation of the support shaft of the rolling component may be locked, for example, because the support shaft of the rolling component moves along the guide portion, an inclination angle thereof becomes maximum, and therefore, a ball support shaft on a fixed carrier side might be bitten into a bottom of the guide portion. That is, there is a possibility that the power may not be transmitted or the gear ratio may not be changed after the transmission of the power during the reverse rotation of the first and second power transmission components.