Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-06-12
2002-07-16
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S200000, C546S244000, C558S017000, C558S018000, C558S019000, C564S230000, C564S231000, C564S237000, C564S238000, C525S326200, C525S327700, C525S328300, C525S333500, C525S333600, C525S393000, C530S345000, C530S408000
Reexamination Certificate
active
06420556
ABSTRACT:
TECHNICAL FIELD
The subject invention relates to methods for synthesizing guanidine compounds, using a solid-support resin to facilitate purification of intermediates and compounds.
BACKGROUND OF THE INVENTION
Solid supported combinatorial chemistry methods have proven to be useful for small molecule based library construction. Substituted guanidine compounds are well known to be responsible for the basis of a variety of phannacological responses (e.g. anti-hypertensive, cardiotonic, H
2
antagonist/agonist, adrenoreceptor agonists, H+/K+ ATPase inhibition, NO synthase inhibition. anti-tumor activity), and there are several examples which have resulted in marketed drug substances.
Examples of guanidine synthesis processes are disclosed in the following references: Robinson, S.; Roskamp, E. J.
TetrahedronLett
. 1997, 53(19), 6697-6705; Yong, Y. F.; Kowalski, J. A.; Lipton. M. A.
J. Org. Chem
. 1997, 62, 1540-1542; Kowalski, J.; Lipton, M. A.
TetrahedronLett
. 1996, 37(33), 5839-5840; Drewry, D. H.; Gerritz, S. W.; Linn, J. A.
TetrahedronLett
. 1997. 38(19), 337-3380; Wang, F.; Hauske, J. R.
TetrahedronLett
. 1997, 38, 8651-8654; Kearney, P. C.; Fernandez, M.; Flygare, J. A.
TetrahedronLett
. 1998, 39, 2663-2666; Dodd, D. S.; Wallace, O. B.
TetrahedronLett
. 1998, 39, 5701-5704; Josey, J. A.; Tarlton, C. A.; Payne, C. E.
TetrahedronLett
. 1998, 39, 5899-5902; Stephensen, H.; Zaragoza, F.
J. Org. Chem
. 1997, 62, 6096-6097. Similar solution phase guanidine chemistries: Atwal, K. S.; Ahimed, S. Z.; O'Reilly, B. C.
TetrahedronLett
. 1989, 30 (52), 7313-7316; Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z.
TetrahedronLett
. 1992, 33 (40), 5933-5936; Kim, K. S.; Qian, L.
TetrahedronLett
. 1993, 34 (48), 7677-7680; Levallet, C.; Lerpiniere, J.; Ko, S. Y.
Tetrahedron
1997, 53, 5291-5304; Barvian, M. R.; Showalter, H. D. H.; Doherty, A. M.
TetrahedronLett
. 1997, 38 (39), 6799-6802.
Examples of resin preparations are disclosed in the following references: Lorsbach, B. A.; Miller, R. B.; Kurth, M. J.
J. Org. Chem
. 1996, 61, 8716-8717; Panek, J. S.; Zhu, B.
TetrahedronLett
. 1996, 37(45), 8151-8154.
OBJECTS OF THE INVENTION
It is an object of the subject invention to provide processes for making guanidine compounds that would be general enough to provide access to a variety of different types in this series and take advantage of the large number of commercially available and diverse amine-based building blocks in both aliphatic and aromatic categories via a traceless linker strategy.
SUMMARY OF THE INVENTION
The subject invention involves processes for making guanidine compounds:
and related cyclized compounds:
using a solid-support resin, comprising the following steps:
(b) reacting an acyl isothiocyanate resin:
with a primary amine:
R
1
—NH
2
, (3)
wherein R
1
is selected from —R, —C(O)R, —CO
2
R, —C(O)NHR, —C(O)NR
2
, NHR, and NR
2
, to provide:
(c) reacting the product from Step (b) with a sulfur activating agent and ammonia or a primary or secondary amine:
wherein R2 and R3 are each independently selected from hydrogen, alkyl, aryl, and heterocycle, to provide:
or, if R
3
contains a displaceable group:
wherein
is derived from R
3
, A being selected from alkylene, arylene, and alkarylene, and B being, nil or one or more non-hydrogen substituents selected from —R, —OH, —OR, —SH, —SR, —NH
2
, —NHR, —NR
2
, ═O, and ═S; wherein, in Steps (a), (b), and (c), R is alkyl, aryl or heterocycle;
(d) treating the product from step (c) with a strong base or medium strength acid to cleave product from the resin, providing the guanidine compound or/and the related cyclized compound.
The subject invention also involves novel acyl isothiocyanate resins and processes for preparing them.
DETAILED DESCRIPTION OF INVENTION
As used herein unless specified otherwise, “alkyl” means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term “alkyl” may be used alone or as part of another word where it may be shortened to “alk” (e.g., in alkoxy, alkylacyl). Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms; most preferred are methyl or ethyl. Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about ten carbon atoms, more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused, spiro, or bridged hydrocarbon rings. Preferred alkyl are unsaturated with from one to about three double or triple bonds, preferably double bonds; more preferably they are mono-unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as “alkanyl”. Alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as “alkenyl”. Preferred substituents of alkyl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted alkyl are preferred.
As used herein, “heteroatom” means a nitrogen, oxygen, or sulfur atom.
As used herein, “alkylene” means an alkyl which connects two other moieties, “heteroalkylene” means an alkylene having one or more heteroatoms in the connecting chain.
As used herein unless specified otherwise, “aryl” means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted. The term “aryl” may be used alone or as part of another word (e.g., in aryloxy, arylacyl). Preferred aryl have from six to about fourteen, preferably to about ten, carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred is phenyl. Preferred substituents of aryl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted aryl are preferred.
As used herein unless specified otherwise, “heterocycle” means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused, spiro, or bridged rings) with one or more heteroatoms in the hydrocarbon ring(s). Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms in the ring(s). Preferred heterocycles have from three to about fourteen, preferably to about ten, carbon plus heteroatoms in the ring(s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the ring(s); and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms. Preferred heterocycles have one ring, but may have two, three, or more, fused spiro, or bridged rings. More preferred heterocycle rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5- or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C; or with one, two or three ring atoms being N and the others being C. Such preferred 5- or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred 5- or 6-ring atom heterocycles are preferably a single ring; or fused with a 3- to 6-ring atom hydrocarbon ring which is saturated, unsaturated with
Davis Brian J.
Echler Sr. Richard S.
Graff, III Milton B.
The Procter & Gamble & Company
Upite David V.
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