WO1997026880A2

WO1997026880A2 - Use of a combination of delavirdine and one or more protease inhibitors in hiv-1 infected patients

Info

Publication number: WO1997026880A2
Application number: PCT/US1996/019222
Authority: WO
Inventors: William W. Freimuth
Original assignee: Pharmacia and Upjohn Co; Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1996-01-26
Filing date: 1996-12-10
Publication date: 1997-07-31
Anticipated expiration: 1998-07-26
Also published as: CA2242761A1; WO1997026880A3; AU1820397A; JP2000503986A; AU723563B2; EP0877613A2

Abstract

Disclosed is a method of treating a human infected with the HIV-1 virus who is in need of such treatment which comprises administering to the infected human an HIV-1 effective amount of delavirdine as in formula (I) or pharmaceutically acceptable salt thereof and an HIV-1 effective amount of one or more protease inhibitors.

Description

USE OF A COMBINATION OF DELAVIRDINE AND ONE OR MORE PROTEASE INHIBITORS IN HIV- 1 INFECTED PATIENTS

BACKGROUND OF THE INVENTION 1. Field of the Invention

The invention is the use of delavirdine with protease inhibitors) for the treatment of humans infected with HIV-1.

2. Description of the Related Art Delavirdine is known, see International Publication No. WO91/09849 based on PCT application PCT/US90/07390.

The following protease inhibitors are known to be useful in treating HIV-1 positive humans.

Saquinavir is known, see US Patent 5,196,438, EXAMPLE 2. Only a very few agents (either alone or in combination) have been approved by regulatory authorities around the world for the treatment of HIV-1 positive individuals. These agents include AZT (ZDV), ddl, ddC, saquinavir, d4T and 3TC all of which are nucleoside agents. In addition, the protease inhibitor saquinavir has been approved for treatment of HTV-l positive individuals. It is known that delavirdine, and/or its metabolites, inhibits the metabolitic enzyme P-450 3A in vivo, see the 9th International Conference on Cytochrome P450, Zurich, Switzerland, 23- 27 July 1995, Mechanism-Based Inactivation of Rat And Human Cytochrome P450 3A By Delavirdine and the Ninth Meeting of the American Association of Pharmaceutical Scientists, Miami, November 6-10, 1995, Correlation Between ERMBT and Oral Exposure to Delavirdine. It is known that saquinavir is metabolized by P-450 3A, see Fourth

International Workshop on HIV Drug Resistance, Sardinia, Italy, July 6-9, 1995, Abstract #68, Reduced sensitivity to Saquinavir: An update on genotyping from Phase I/TI trials. H. Jacobsen, et al as well as the discussion following the presentation. J. Infectious Diseases, 171, 61-7 (1995) discloses that DLV has synergistic antiviral effect with a peptide protease inhibitor.

SUMMARY OF INVENTION Disclosed is a method of treating a human infected with the HIV-l virus who is in need of such treatment which comprises administering to the infected human an HTV-l effective amount of delavirdine or pharmaceutically acceptable salt thereof and an HTV-l effective amount of one or more protease inhibitors. DETAILED DESCRIPTION OF THE INVENTION The invention is a method of treating a human infected with the HTV-l virus who is in need of such treatment which comprises administering to the infected human an HTV-l effective amount of delavirdine or pharmaceutically acceptable salt thereof and an HTV-l effective amount of one or more protease inhibitors. Protease inhibitors are a class of anti-HTV-1 agents which includes saquinavir.

Delavirdine is produced by the procedure of EXAMPLES 1-3. Since delavirdine is an amine base it is known to those skilled in the art how to prepare salts of these amine bases. The amine bases form acid addition salts when reacted with acids of sufficient strength to produce the corresponding salts. The salts are preferred over the free amines since they produce compounds which are more water soluble and more crystalline. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The preferred pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, p- toluenesulfonic, benzenesulfonic, CH₃-(CH₂)_n-COOH where n is 0 thru 4, HOOC- (CH₂)_n-COOH where n is as defined above.

It is preferred that delavirdine be the mesylate salt. Further, it is preferred that delavirdine mesylate be present as the "S" or "T" crystal form, more preferably as the "T" form. These salts are prepared as follows. The "S" crystal form (also known as form VTII) of delavirdine is produced by starting with delavirdine 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 delavirdine monomethanesulfonate salt crystallizes, it is filtered and dried as is known to those skilled in the art.

When the "S" crystal form of delavirdine monomethanesulfonate salt is desired, it is preferred to dissolve the delavirdine 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 delavirdine 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 delavirdine free base and produce the methanesulfonic acid salt at the same time as the crystallization, see EXAMPLES 6 and 12, 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 5, 8 and 10 are preferred. When it is desired to start with the free base and acetonitrile as the dissolving solvent, at temperatures below 40° 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 delavirdine monomethanesulfonate salt is produced by starting with delavirdine 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 delavirdine 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" foπn 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.

Saquinavir is known (US Patent 5,196,438, EXAMPLE 2) to be useful in treating individuals that are HTV-l positive. See US Patent 5,196,438 for a discussion of how to treat individuals that are HTV-l positive.

The method of the present invention is the use of delavirdine with one or more one protease inhibitors to treat HTV-l infected humans. It is preferred that both the delavirdine and protease inhibitor be given orally. The administration of delavirdine and the protease inhibitors) can be in one dosage unit or in separate dosage units. If different dosage units are used, they may be administered at the same time of the day or at different times. The important thing is for the patient within a 24 hr period to have taken an HTV-l effective amount of delavirdine (or pharmaceutically acceptable salt thereof) and an HTV-l effective amount of a protease inhibitor. The advantage of administering the delavirdine and protease inhibitor separately is that the dosages of each can be varied without varying the other. In addition, DLV and saquinavir can be used in combination with nucleoside reverse transcriptase inhibitors (RTIs) such as ZDV, ddl, ddC or D4T at their approved and recommended doses.

The use of both DLV and saquinavir alone to treat HTV-l positive individuals is known, see International Publication No. WO91/09849 and US Patent 5,196,438, respectively. The method of the present invention is practiced by administering DLV with, or prior to the administration of saquinavir. When delavirdine and saquinavir are used together according to the method of the present patent apphcation it is preferred that delavirdine and saquinavir be administered as follows. The two agents, DLV and saquinavir are both administered daily to the patient as long as the patient is being treated. DLV is administered from about 100 to about 1,000 mg, one to four times daily, preferably from about 100 to about 3,000 mg day, more preferably from about 500 to about 2,000 mg/day, even more preferably about 400 mg three times daily. Saquinavir is administered from about 200 to about 800 mg one to four times daily, preferably from about 200 to about 3,200 mg/day, more preferably from about 1,000 to about 2,000 mg day, even more preferably about 600 mg three times daily. DLV can be given orally with or without food, but saquinavir is best absorbed with food.

When delavirdine and saquinavir are used together according to the method of the present invention in treating humans who are HTV-l positive it is used the same regardless of whether the patient is asymptomatic or symptomatic and whether the CD4 count is below 500/mm³ or above 500/mm³. The delavirdine and saquinavir can be given either at the same time or at different times during the day. They need not be given at the same frequency of administration. For example delavirdine may be administered three times daily and the saquinavir four times daily. However, it is preferred that frequency of administration for both the delavirdine and saquinavir be the same, preferably 3 or 4 times daily. Many HTV-l positive individuals will be treated with DLV, saquinavir in combination with other anti-HTV-1 agents such as ZDV, ddl, ddC, 3TC or d4T at their approved and recommended doses.

The exact dosage and frequency of administration of delavirdine and the protease inhibitor depends on the particular protease inhibitor used as well as other factors.. The exact dose of delavirdine and of the protease inhibitors also depends on the severity of the HTV-l infection, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art. This dose can also be determined by measuring the blood level or concentration of delavirdine and the particular protease inhibitors) used, The exact dose of delavirdine and the protease inhibitor(s) can also be more accurately determined by measuring various surrogate markers such as CD4 and viral burden as is known to physicians who treat individuals infected with HTV-l. It is also important to adjust the dose depending on the patient's response to the treatment.

DEFINITIONS Delavirdine refers to l-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-( 1- methylethylamino)-2-pyridinyl]piperazine also known as DLV.

Saquinavir is CAS #127,779-20-8 and refers to (S)-N-[(αS)-α-[(lR)-2- [(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2(lH)-isoquinolyl]-l- hydroxyethyl]phenethyl]-2-quinaldamido succinamide, also known as N-tert- butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(s)-[[N-(2-quinolylcarbonyl)-L- asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide.

Indinavir refers to [l(lS,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-lH- inden-l-yl)-5-[2-[[(l,l-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-l- piperazinyl]-2-(phenylmethyl)-D-erythropentanamide. Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. Pharmaceutically acceptable anion salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH₃-(CH₂)_n-COOH where n is 0 thru 4, HOOC- (CH₂)n-COOH where n is as defined above.

NNNNNN-NN-N refers to Chemical Abstracts Service (CAS, Columbus, Ohio) registry numbers where each "N" is an integer from 0 thru 9, but deleting leading zeros in the 6-digit portion of the number. Registry numbers are assigned to a particular chemical compound by CAS criteria, provided that the compound has been found to exist and it has been characterized in some way. Compounds published from approximately 1967 to the present are registered publicly and the registry number is the key to finding references in the CAS data base for such a registered compound. The CAS data base is publicly available from several database vendors such as STN International, System Development Corporation (SDC) Orbit Search Service, Lockheed Dialog, Bibliographic Retrieval Systems, Questrel, etc. CAS registry numbers are included in the EXAMPLES for some of the compounds which have been registered. EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

PREPARATION 1 l-[5-Methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]- piperazine, hydrochloride l-(Ethyl)-3-(dimethylaminopropyl)carbodiimide (1.25 g) is added to a solution of l-(3-ethyl-2-pyridinyl)piperazine (1.12 g) in THF (15 ml). The reaction is stirred at 20-25° for 3 hr, then it is dissolved in chloroform (50 ml) and extracted with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatog¬ raphy (200 g silica) eluting with ethyl acetate hexane (50/50), the appropriate fractions are pooled and concentrated to give the title compound, The product is dissolved in methanol ( 150 ml) with heating, cooled to 20-25° and chlorotrimethyl- silane (4.70 mmol) is added. The mixture is concentrated to half-volume, ether is added until cloudy and the flask is stored at 0° overnight. Filtration gives the hydrochloride salt, mp 194-195°. CMR (300 MHz, CDC1₃) 165.2, 155.9, 146.1, 144.8, 133.4, 130.5, 128.9, 125.6, 122.6, 116.7, 113.9, 106.5, 103.3, 56.3, 39.1 and 14.2 δ.

The mesylate salt is formed by dissolving the free base in methanol and methanesulfonic acid ( 1 eq) is added. The solution is diluted with diethyl ether until the salt crystallizes out of solution. The crystals are collected and dried to afford the mesyl salt of the title compound, mp 215-216°, CMR (300 MHz, CD₃OD) 165.22, 156.03, 146.23, 141.75, 133.35, 130.6, 129.0, 125.7, 123.5, 122.5, 166.6, 113.9, 106.5, 103.2, 56.2, 45.7, 39.7, 39.0 and 14.1 δ.

EXAMPLE 1 l-[5-Nitroindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2- pyridinyljpiperazine Following the general procedure of PREPARATION 1 and making non-critical variations but starting with 5-nitroindole-2-carboxylic acid (0.86 g), l-[3-(N-isopropyl)amino)-2-pyridinyl]piperazine (0.43 g), l-(ethyl)-3-(di- methylaminopropyDcarbodiimide (0.45 g) and THF (4 ml), the title compound is obtained, mp 153-154°. EXAMPLE 2 l-[5-Aminoindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2- pyridinyljpiperazine l-[5-Nitroindolyl-2-carbonyl]-4-t3-(l-methylethylamino)-2-pyridinyl]piperazine (EXAMPLE 1, 1.0 g) is dissolved in ethanol (60 ml) and THF (60 ml) and palladium on carbon (10%, 0.15 g) is added. The reaction is hydrogenated at 40 psi for 14 hr, then filtered through celite and concentrated under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate/hexane (50/50 — > 75/25), pooling and concentrating the appropriate fractions gives the title compound, mp 212-214°. EXAMPLE 3 l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l- methylethylamino)-2-pyridinyl]piperazine l-[(5-Ammoindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2-pyridinyl]piper- azine (EXAMPLE 2, 0.075 g) is dissolved in methylene chloride (0.4 ml) and pyridine (0.016 g) is added and the reaction is cooled to 0°. Then methanesulfonyl chloride (0.023 g) is added. After 2.5 hr of stirring, the reaction is diluted with chloroform and washed with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is dissolved in the minimum amount of chloroform and passed through a small plug of silica gel and then it is recrystallized with ethyl acetate/hexane to provide the title compound, mp 226-228°. EXAMPLE 4 l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l- methylethylamino)-2-pyridinyl]piperazine mesylate l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl3piperazine (EXAMPLE 3, 90 mg, 0.197 mmmol) in 1.0 mL of acetonitrile ( 1 Ml) and added methanesulfonic acid (12.8 uL). The mixture is heated on a steam bath until the solids are dissolved. An oil formed immediately upon removal from the steam bath, but then the oil crystallizes on standing. The crystals formed are used as seed crystals in the scaled-up procedure below. l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl]piperazine (5.63 g, 12.3 mmol) is suspended in acetonitrile (70 mL) and methanesulfonic acid (1 eq.) is added. The mixture is heated on the steam bath and sonicated until the solids are dissolved. Then the mixture is slowly cooled and a seed crystal is added. Filtration and drying under reduced pressure at 90° gives the title compound, mp = 162-165°; IR (mineral oil) 3349, 3302, 3007, 1635, 1628, 1603, 1559, 1532 cm ¹; NMR (300 MHz, CD₃OD) 7.63, 7.55, 7.46-7.40, 7.17, 6.89, 4.16, 3.79, 3.43, 2.90, 2.70 and 1.32 δ; CMR (300 MHz, CD₃OD) 164.9, 146.3, 140.9, 136.0, 131.9, 131.5, 128.9, 125.8, 124.4, 122.5, 121.9, 116.7, 113.8, 106.5, 39.7, 38.7 and 22.1 δ.

EXAMPLE 5 "S" Crystal Form Of l-[5-methanesulfonamidoindolyl-2-carbon- yl]-4-[3- ( l-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt From A Different Crystal Form l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-( 1-methylethyl- amino)-2-pyridinyl]piperazine monomethanesulfonate salt (crystal form XI, 25 g) is dissolved in methanol (125 ml) by refluxing. The mixture is concentrated atmospherically to a volume of 40-45 ml. While maintaining reflux, warm acetone (100 ml) is added over 5 min. The mixture is held at reflux and crystals are observed within 30 min. The slurry is stirred at reflux for a total of 60 min and then filtered. The filter cake is washed with acetone ( 100 ml) and dried to give the title compound, mp 228-232°.

EXAMPLE 6 "S" Crystal Form Of l-[5-methanesulfonamidoindolyl-2-carbon- yl]-4-[3- ( l-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt From The Free Base l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl]piperazine (THF solvate, 100 g, 0.18 moles) is slurried in methanol to which is added methanesulfonic acid (19.6 g, 0.20 moles). The mixture is warmed to 40° and isopropanol (325 ml) is added. The mixture is held at 37-42° and crystals are observed within 2-3 hours. The slurry is cooled over 2 hr to 15° and filtered. The cake is washed with isopropanol (100 ml) and methyl-t-butyl ether (250 ml) then dried to give the title compound, mp 221-228°.

EXAMPLE 7 "S" Crystal Form Of l-[5-methanesulfonamidoindolyl-2-carbon- yl]-4-[3- ( l-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt From The Free Base l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl]piperazine (THF solvate, 6.58 kg, 12.77 moles) in methanol (50 1) and methylene chloride (150 1) is filtered through a 0.6 micron filter, then rinsed with methylene chloride (50 1). The mixture is concentrated under reduced pressure at 10° to 10 1, diluted with acetonitrile (160 kg) and concentrated to 10 1. The residue is then slurried in acetonitrile (240 1), the mixture is heated to 63° and methanesulfonic acid (1.29 kg, 13.4 moles) is added. The mixture is heated further to 70-75° and after stirring at that temperature for 4.5 hr it is cooled to 32°. The product is collected on a filter, rinsed with acetonitrile (50 1) and dried to give the title compound, mp 222-229°. EXAMPLE 8 "T" Crystal Form Of l-[5-methanesulfonamidoindolyl-2-carbon- yl]-4-[3- ( l-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt From Crystal Form VIII l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl]piperazine monomethanesulfonate salt (crystal form VIII, 25.0 g, 0.045 moles) is dissolved in methanol (25 ml) at reflux. After an hour at reflux crystals are observed. The slurry is filtered without cooling and dried to give the title compound, mp 213-233°.

EXAMPLE 9 "T" Crystal Foπn Of l-[5-methanesulfonamidoindolyl-2-carbon- yl]-4-[3-(l-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt From The Free Base l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl]piperazine (THF solvate, 100.0 g, 0.18 moles) is slurried in methanol (250 ml) to which is added methanesulfonic acid (19.0 g, 0.21 moles). The mixture is heated at reflux until dissolved and then concentrated atmospherically to 150 ml volume. The mixture is seeded with 10 mg of previously isolated "T" crystal form and reflux is continued until crystallization is observed. The slurry is held at reflux for 16 hr and filtered without cooling and dried to give the title compound. EXAMPLE 10 "T" Crystal Form Of l-[5-methanesulfonamidoindolyl-2- carbonyl]-4-[3-(l-methylethylamino)-2-pyridinyl]- piperazine monomethanesulfonate salt From Crystal

Form VIII l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2- pyridinyljpiperazine monomethanesulfonate salt (crystal form VIII, 104.9 g, 0.19 moles) is dissolved in methanol (150 ml) by refluxing. The solution is concentrated atmospherically to a 175 ml volume. While maintaining reflux, warm acetone (100 ml) is added over 15 minutes. Crystals are observed within 30 minutes at which time additional acetone (175 ml) is added over 70 minutes. The slurry is stirred at reflux for a total of 2 hr, cooled to 15°, and then filtered. The filter cake is washed with acetone (200 ml) and dried to give the title compound, mp 212-228°. EXAMPLE 11 "T" Crystal Form Of l-[5-methanesulfonamidoindolyl-2- carbonyl]-4-[3-( l-methylethylamino)-2-pyridinyl]- piperazine monomethanesulfonate salt From Crystal Form VIII l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2- pyridinyljpiperazine monomethanesulfonate salt (crystal form VIII, 25.0 g, 0.045 moles) is slurried at reflux in a mixture of methanol/acetone (1/1, 50 ml). The slurry is seeded with 10 mg of previously isolated "T" crystal form. After refluxing for 2-3 hr the slurry is cooled to 15°, filtered, washed with acetone (50 ml) and dried to give the title compound, mp 213-228°. EXAMPLE 12 "T" Crystal Form Of l-[5-methanesulfonamidoindolyl-2- carbonyl]-4-[3-( l-methylethylamino)-2-pyridinyl]- piperazine monomethanesulfonate salt l-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2- pyridinyl]piperazine (free base, THF solvate, 100.0 g, 0.18 moles) is slurried in methanol (250 ml) to which is added methanesulfonic acid (17.65 g, 0.18 moles). The mixture is heated at reflux until dissolved and then concentrated atmospherically to about 300 ml volume at which time it is seeded with 10-15 mg of previously isolated l-t5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-( 1-methylethyl- amino)-2-pyridinyl]piperazine monomethanesulfonate salt "T" crystal form. The atmospheric concentration is continue to a 200 ml volume. While maintaining reflux, acetone (175 ml) is added over about 10 minutes. The mixture is seeded again with 10-15 mg of previously isolated l-[5-methanesulfonamidoindolyl-2-carbon- yl]-4-[3-( l-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt "T" crystal form and held at reflux. Crystals are observed within 30 minutes and the slurry is maintained at reflux for an additional 30 minutes. At that time the atmospheric distillation is restarted and acetone is added so as to maintain a constant volume. When 250 ml of acetone had been added the distillation is ended and the mixture cooled to 15°. After stirring the slurry for about two hours it is filtered and the filter cake is washed with acetone. The product is dried to give 88.96 g of the title compound, mp 214-227°. EXAMPLE 13 Use of delavirdine and saquinavir

An asymptomatic 22 year old 70 kg male who is HTV-l positive has a CD4 count of 800/mm³. He is administered delavirdine 400 mg three times daily and saquinavir 600 mg three times daily. The saquinavir is administered or taken by the patient simultaneously with the delavirdine. EXAMPLE 14 Use of delavirdine and saquinavir

A symptomatic 31 year old 62 kg female who is HTV-l positive has a CD4 count of 220/mm³. She is administered delavirdine 400 mg four times daily and saquinavir mg 800 mg three times daily. The saquinavir is administered or taken by the patient 2 hr after the delavirdine.

CHART A l-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(l-methylethyl- amino)-2-pyridinyl]piperazine has the following chemical structural formula

Claims

1. A method of treating a human infected with the HTV-l virus who is in need of such treatment which comprises administering to the infected human an HTV-l effective amount of delavirdine or pharmaceutically acceptable salt thereof and an HTV-l effective amount of one or more protease inhibitors.

2. A method of treating a human infected with the HTV-l virus according to claim 1 where one protease inhibitor is used.

3. A method of treating a human infected with the HTV-l virus according to claim 1 where the protease inhibitor is saquinavir or pharmaceutically acceptable salt thereof.

4. A method of treating a human infected with the HTV-l virus according to claim 1 where the effective amount of delavirdine is from about 100 mg/day to about 3,000 mg/day.

5. A method of treating a human infected with the HTV-l virus according to claim 4 where the effective amount of delavirdine is from about 500 mg/day to about 2,000 mg/day.

6. A method of treating a human infected with the HTV-l virus according to claim 1 where the effective amount of saquinavir is from about 200 mg/day to about 3,200 mg/day.

7. A method of treating a human infected with the HTV-l virus according to claim 6 where the effective amount of saquinavir is from about 1,000 mg/day to about 2,000 mg/day.

8. A method of treating a human infected with the HTV-l virus according to claim 1 where delavirdine is present as delavirdine mesylate.

9. Use of delavirdine or pharmaceutically acceptable salt thereof to prepare a medicament to treat a human infected with the HTV-l virus who is in need of such treatment, where the medicament is administered with one or more protease inhibitors.

10. Use according to claim 9 where one protease inhibitor is used.

11. Use according to claim 9 where the protease inhibitor is saquinavir or pharmaceutically acceptable salt thereof.

12. Use according to claim 9 where the effective amount of delavirdine is from about 100 mg/day to about 3,000 mg/day.

13. Use according to claim 9 where the effective amount of delavirdine is from about 500 mg/day to about 2,000 mg/day.

14. Use according to claim 9 where the effective amount of saquinavir is from about 200 mg/day to about 3,200 mg/day.

15. Use according to claim 9 where the effective amount of saquinavir is from about 1,000 mg/day to about 2,000 mg/day.

16. Use according to claim 9 where delavirdine is present as delavirdine mesylate.