Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1996-09-30
2002-09-17
Bernhardt, Emily (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C514S253090
Reexamination Certificate
active
06452007
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the invention is crystal forms of a known compound, 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-pyridinyl]piperazine monomethanesulfonate salt, which is a pharmaceutical useful in treating individuals who are HIV positive.
2. Description of the Related Art
It is known to those skilled in the art that solids including pharmaceuticals often have more than one crystal form and this is known as polymorphism. Numerous examples are cited in the standard references of solid state properties of pharmaceuticals, Byrn, S. R., Solid-State Chemistry of Drugs, New Your, Academ. Press (1982); Kuhnert-Brandstatter, M., Thermomiscroscopy In The Analysis of Pharmaceuticals, New York, Pergamon Press (1971) and
J. Pharm. Sci.,
58, 911 (1969). Byrn states that, in general, polymorphs exhibit different physical characteristics including solubility and physical and chemical stability. It is important to note that there is no reliable method to predict the observable crystal structures of a given drug or to predict the existence of polymorphs with desirable physical properties.
U.S. Pat. No. 3,565,924 discloses and claims 25-hydroxycocalciferol (25-HCC) which is a solid. Even in view of this prior art the United States Patent Office allowed U.S. Pat. No. 3,833,622 to a novel crystal form 25-HCC hemihydrate.
U.S. Pat. No. 4,521,431 discloses forms 1 and 2 of ranitidine hydrochloride.
U.S. Pat. No. 4,504,657 claims “crystalline 7-[D-&agr;-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate.
International Publication No. WO 91/09849 (EXAMPLE 105) discloses 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine.
Antimicrobial Agents
&
Chemotherapy,
1127-31 (May 1993) discloses 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine free base. The
Journal of Medicinal Chemistry,
36, 1505 (1993) discloses 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in the “S” crystal form.
SUMMARY OF INVENTION
Disclosed is 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt known as the “S” form with a powder X-ray diffraction spectrum of that set forth in the claims.
Also disclosed is 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt known as the “T” form with a powder X-ray diffraction spectrum of that set forth in the claims.
DETAILED DESCRIPTION OF THE INVENTION
1-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl)-piperazine is known, see International Publication No. WO 91/09849 (EXAMPLE 105). 1-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is also known, see
Journal of Medicinal Chemistry,
36, 1505 (1993) and
Antimicrobial Agents
&
Chemotherapy,
1127-31 (May 1993).
The “S” crystal form (also known as form VIII) of 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is produced by starting with 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in other than the “S” form and dissolving it in a dissolving solvent selected from the group consisting of methanol, ethanol, acetonitrile, dimethyl sulfoxide and dimethylformamide or mixture thereof; it is preferred that the dissolving solvent is methanol. When starting with the free amine, methylene chloride can be used as a co-dissolving solvent preferably with methanol, but alone will not appreciably dissolve the starting material. To the solution of the salt in the dissolving solvent is added a sufficient quantity of crystallizing solvent, or mixtures thereof, which is selected from the group consisting of acetone, acetonitrile, isopropanol, n-propanol, methyl t-butyl ether, toluene, ethyl acetate, n-propyl acetate, i-propyl acetate, tetrahydrofuran, toluene or any isomer of xylene, hexane or heptane; it is preferred that the crystallizing solvent be acetone. It is preferred to add a very small amount of the desired crystal form as it hastens crystallization of the desired “S” form. After the 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt crystallizes, it is filtered and dried as is known to those skilled in the art.
When the “S” crystal form of 1-[5-methanesulfonamidoindolyl-2-carbon-yl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is desired, it is preferred to dissolve the 1-[5-methanesulfonamidoindolyl-2-carbon-yl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in methanol to give a concentration of about 1 g of compound/5 ml of methanol. This mixture is then concentrated atmospherically to a concentration of about one molar by reflux. While maintaining reflux, acetone (about 4 ml/g of 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt) is added over a short period, for example five or ten minutes. At this point it is desirable and preferred to seed the crystallization with a small amount of the “S” crystal form. The mixture is stirred at reflux until crystallization occurs. The mixture can be filtered while hot or cooled.
An alternative procedure is to start with 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine free base and produce the methanesulfonic acid salt at the same time as the crystallization, see EXAMPLEs 2 and 8, which is the preferred method of practicing the invention on large scale. For small scale (laboratory or bench size) and infrequent runs the processes of EXAMPLEs 1, 4 and 6 are preferred.
When it is desired to start with the free base and acetonitrile as the dissolving solvent, at temperatures below 400 a solvated crystal form is produced. On drying, the acetonitrile is removed from the solid product and a desolvated crystal form results. When starting with the free base and methanol as the dissolving solvent and using isopropanol as the crystallizing solvent, none of the undesired crystal form that occurs with acetonitrile and low temperature occurs, but the crystals can agglomerate which can make drying more difficult. When acetone is used as the crystallizing solvent, the agglomeration problem does not occur.
The “T” crystal form (also known as form XI) of 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is produced by starting with 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in other than the “T” form and recrystallizing from a dissolving solvent (as identified above). The use of a crystallizing solvent (identified above) is optional. The “T” form of 1-(5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt can be produced from either the free base or a different crystal form of the mesylate salt as is described above for the “S” crystal form. For obtaining the “T” form it is preferred to have a concentration of about 1 g of compound/ml of dissolving solvent, especially when the dissolving solvent is methanol. When producing the “T” crystal form, it is preferred to seed the reaction mixture with previously obtained “T” crystal.
Both “S” and “T” forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylet
Bergren Michael S.
Havens Jeffrey L.
Lyster Mark A.
Smith Donald P.
Bernhardt Emily
Pharmacia & Upjohn Company
Stein Bruce
LandOfFree
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