CA2030433C - New isoquinoline- carboxamide amino acid derivatives useful for treatment of viral diseases - Google Patents
New isoquinoline- carboxamide amino acid derivatives useful for treatment of viral diseasesInfo
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- CA2030433C CA2030433C CA002030433A CA2030433A CA2030433C CA 2030433 C CA2030433 C CA 2030433C CA 002030433 A CA002030433 A CA 002030433A CA 2030433 A CA2030433 A CA 2030433A CA 2030433 C CA2030433 C CA 2030433C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
Compounds of the general formula (see fig.I) wherein R represents benzyloxycarbonyl or 2-quinolylcarbonyl, and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and can be used as medicaments for the treatment or prophylaxis of viral infections. They can be manufactured according to generally known procedures.
Description
2~3~4~
The present invention is concerned with amino acid derivatives.
The amino acid derivatives provided by the present invention are compounds of the general formula ~ ~ ~
NH2 NHC(CH3)3 wherein R represents benzyloxycarbonyl or 2-quinolylcarbonyl, and pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I and their pharmaceutically acceptable acid addition salts are novel and possess valuable pharmacological properties. In particular, they inhibit proteases of viral origin and can be used in the prophylaxi6 or treatment of viral infections, particularly of infections caused by HIV and other retroid viruses.
Objects of the present invention are the compounds of Kbr/30.8.90 2~3~433 formula I and their aforementioned salts per se and for use as therapeutically active substance6, a process for the manufacture of said compounds and salts, intermediates used in said process, medicaments containing said compounds and salts, the use of said compounds and salts in the control or prevention of illnesses, especially in the treatment or prophylaxis of viral infections, and the use of said compounds and salts for the manufacture of medicaments for the treatment or prophylaxis of viral infections.
The pharmaceutically acceptable acid addition salts of the compounds of formula I are salts formed with inorganic acids, for example hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc, or with organic acids, for example acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid etc.
According to the process provided by the present invention, the compounds of formula I hereinbefore and their pharmaceutically acceptable acid addition salt6 are manufactured by (a) reacting 2-[(3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N--tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide of the formula 2 03~43~
~ ) H2N ~ ~ II
o NHC(CH3)3 with an acid of the general formula H ¦¦
~ N ~ C OH
20 ~ III
'ro ;~H2 wherein R has the fiignificance given earlier, or a reactive derivative thereof, or (b) reducing a compound of the general formula - 4 - ~3'Q4~3 o r~
~H~ IV
~ro ~
NH2 NHC(CH3)3 wherein R has the significance given earlier, and separating the desired 2(R)-hydroxy isomer from the mixture obtained, or (c) reacting 2-t3(S)-r(L-asparaginyl)amino]-2(R)-hydroxy--4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-iso-quinoline-3(S)-carboxamide of the formula 2S ~
H2N~ ~ V
'r~ ~
NH2 ~ ~tHC(CH3)3 with an agent yielding the benzyloxycarbonyl or 20~0~3~
2-quinolylcarbonyl group, and (d) if desired, converting a compound of formula I
obtained into a pharmaceutically acceptable acid addition salt.
The reaction of a compound of formula II with an acid of formula III in accordance with embodiment (a) of the process can be carried out in accordance with method6 known per se in peptide chemistry. Thus, when an acid of formula III is used, the reaction is preferably carried out in the presence of a condensation agent such as hydroxybenzotriazole and dicyclohexylcarbodiimide. Thi6 reaction is conveniently carried out in an inert organic solvent such as an ether (e.g. diethyl ether, tetrahydro-furan etc) or dimethylformamide at a low temperature, suitably at about -10~C to +5~C and especially at about 0~C. Suitable reactive derivatives of acids of formula III
which can be used are, for example, the corresponding acid halide6 (e.g. acid chlorides), acid anhydrides, mixed anhydrides, activated ester6 etc. When a reactive derivative is used, the reaction is conveniently carried out in an inert organic solvent such as a halogenated aliphatic hydrocarbon (e.g. dichloromethane etc) or an ether (e.g. diethyl ether, tetrahydrofuran etc) and, where appropriate, in the presence or an organic base (e.g.
N-ethylmorpholine, diisopropylethylamine etc) at a low temperature, suitably at about -10~C to +5~C and especially at about 0~C.
The reduction of a compound of formula IV in accordance with embodiment (b) of the proces6 can be carried out according to methods known per se for the reduction of a carbonyl group to a hydroxy group. Thus, 35 for example, the reduction can be carried out using a complex metal hydride such as an alkali metal borohydride, - 6 - 2D3 ~33 especially sodium borohydride, in an appropriate organic solvent ~uch as an alkanol (e.g. methanol, ethanol, propanol, isopropanol etc). Conveniently, the reduction is carried out at about room temperature. The separation of the desired 2(R)-hydroxy isomer from the mixture obtained can be performed according to conventional methods, e.g.
by chromatography and the like.
In accordance with embodiment (c) of the process, the suitable agent yielding the benzyloxycarbonyl group is benzyl chloroformate. Suitable agent~ which yield the 2-quinolylcarbonyl group are the corre~ponding acid or reactive derivatives thereof such as the corresponding acid halides (e.g. acid chloride), acid anhydride, mixed anhydrides, activated e~ters etc. The reaction of a compound of formula V with the aforementioned agents i~
carried out in the same manner as that described earlier in connection with embodiment (a) of the process.
The conversion of a compound of formula I into a pharmaceutically acceptable acid addition salt in accordance with embodiment (d) of the proce6s can be carried out by treating ~uch a compound in a conventional manner with an inorganic acid, for example a hydrohalic 25 acid 6uch as hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc, or with an organic acid such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methane6ulphonic acid, p-toluenesulphonic acid etc.
The compound of formula II which i6 used as 6tarting material in embodiment (a) of the process is novel and also forms an object of the present invention.
The compound of f ormula II can be prepared, f or example, by reacting a compound of the general formula ~D3a~33 V~
~N~--X
o 10 wherein Rl represents a amino-protecting group (e.g.
tert.butoxycarbonyl or benzyloxyca~bonyl) and X
represents a chlorine or bromine atom, with N-tert.butyl-decahydro-(4aS,8aS)isoquinoline-3(5)--carboxamide of the formula HN/~
o, ~J VII
NHC(CH3) 3 and reducing the resulting compound of the general formula H~-- ~ ~ I I I
o~b~
NHC(CH3)3 203Q~33 wherein R has the significance given earlier, ~eparating the desired 2(R)-hydroxy isomer from the mixture obtained and cleaving off the group R from the S resulting compound of the general formula ~
0~ ~ IX
0~
N~C(C~3)3 wherein R has the significance given earlier, to give a compound of formula II.
The reaction of a compound of formula VI, preferably one in which Rl represents benzyloxycarbonyl, with a compound of formula VII can be carried out in a known manner; for example, in an inert organic ~olvent such a6 a halogenated aliphatic hydrocarbon (e.g. dichloromethane etc) and in the presence of a ba~e (e.g. a tcialkylamine such a~ triethylamine etc), conveniently at about room temperature.
The reduction of a compound of formula VIII to give a compound of formula IX and the sub~equent separation of the desired 2(R)-hydroxy isomer can be carried out as described earlier in connection with embodiment (b) of the process of the invention, i.e. the reduction of a compound of formula IV and the separation of the desired 2(R)--hydroxy isomer from the mixture obtained.
The cleavage of the group Rl from a compound of formula IX can al~o be carried out in a known manner; for example, using a strong inorganic acid such as a hydrohalic acid or a strong organic acid (e.g. trifluoro-acetic acid etc), conveniently at about 0~C to about room temperature. Alternatively, a hydrogenolytically-cleavable amino-protecting group R can be cleaved off using hydrogen in the presence of a noble-metal catalyst (e.g. a palladium catalyst such as palladium-on-carbon) in an organic solvent or solvent mixture which is inert under the reaction conditions (e.g. an alkanol such as ethanol, isopropanol etc, an alkanecarboxylic acid ester such as ethyl acetate, etc) and conveniently at about room temperature.
A further method for the preparation of the compound of formula II comprises firstly reacting a compound of the general formula ~ ~ X
~N~
wherein R has the significance given earlier, with the compound of formula VII hereinbefore, conveniently in an inert organic solvent such as an alkanol (e.g. methanol etc), dimethylformamide or the like 35 and at an elevated temperature, conveniently at about 600C
to about 120~C, and then cleaving off the group R in the reaction product (a compound of formula IX
2 ~ 3 hereinbefore) as described earlier.
The compounds of formula IV which are used as starting materials in embodiment (b) of the process can be prepared, for example, by cleaving off the amino--protecting group R from a compound of formula VIII and reacting the product with an acid of formula III or a reactive derivative thereof. This reaction can be carried out in an analogous manner to that described earlier in connection with embodiment (a) of the process.
The compound of formula V which is used as starting material in embodiments (c) of the process is novel and forms a further object of the present invention.
The compound of formula V can be prepared, for example, by cleaving off the benzyloxycarbonyl group R
from the compound of formula I in which R represents benzyloxycarbonyl or the tert.butoxycarbonyl group form a 20 compound corresponding to formula I but in which R
represents tert.butoxycarbonyl. This latter compound can be prepared, for example, by reacting the compound of formula II with N-(tert.butoxycarbonyl)-L-asparagine in accordance with embodiment (a) of the process. The above 25 cleavage is carried out in a manner analogous to that described earlier in connection with the cleavage of the group R from a compound of formula VIII.
The starting materials of formula III and their 30 reactive derivatives as well as the compounds of formulae VI, VII and X hereinbefore, insofar as they are not known compounds or analogues of known compounds, can be prepared in a similar manner to the known compounds or as described in the Examples hereinafter or in analogy thereto.
35 Moreover, the agents used in embodiment (c) of the process are generally known compounds.
f~
--- 2D3~}33 As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and are useful in the treatment or prophylaxis of viral infections, particularly of infections caused by HIV and other retroid viruses.
The in vitro inhibition of HIV protease by the compounds provided by the present invention can be demonstrated by means of the following test:
HIV protease was expressed in E. coli and partially purified from soluble extracts of the bacterium by ammonium sulphate fractionation (0-30%). Protease activity was assayed using the protected hexapeptide succinyl-Ser--Leu-Asn-Tyr-Pro-Ile isobutylamide (S ) or the protected heptapeptide succinyl-Val-Ser-Gln-Asn-Phe-Pro-Ile isobutylamide (S ) as the substrate. Cleavage of the substrate was quantified by measuring the production of H-Pro-Ile isobutylamide by the spectrophotometric assay of 20 N-terminal proline.
1.25 mM of substrate were dissolved in 125 mM of citrate buffer (pH 5.5) containing 0.125 mg/ml of Tween 20. 10 ~1 of a solution of various concentrations 25 of the test compound (dissolved in methanol or dimethyl sulphoxide and diluted with water containing 0.1%
Tween 20) and 10 ~1 of protease were added to 80 ~1 of the above buffered substrate. Digestion was carried out at 37~C for a fixed period of time and was terminated by the 30 addition of 1 ml of colour reagent r30 ~g/ml of isatin and 1.5 mg/ml of 2-(4-chlorobenzoyl)benzoic acid in 10%
acetone in ethanol (vol./vol.)]. The solution was heated in a water bath and then the pigmented residues were re-dissolved in 1 ml of 1% pyrogallol in 33% water in - -3S acetone (wt./vol./vol.). The optical density of the ~olution was measured spectrophotometrically at 599 nm.
The formation of H-Pro-Ile isobutylamide in the presence *Trademark ~i -- 2O3OL~ 33 of the te6t compound was compared with controls and the concentration of te6t compound required to give 50%
inhibition (I50) wa6 determined by mean6 of a graph plotted from the variou6 concentrations of test compound used.
The in vitro antiviral activity of the compounds of formula I can be demonstrated in the assay described below:
Activity aqainst HIV:
This assay uses HTLV-III (6train RF) grown in C8166 cell6 (a human CD4 T lymphoblastoid line) using RPMl 1640 medium with bicarbonate buffer, antibiotics and 10%
15 foetal bovine serum.
A suspension of cells is infected with ten times the TCD50 ~f virus and ad60rption allowed to proceed for 90 minute6 at 37~C. The cells are washed three times with 20 medium. The test is carried out in 6 ml tis6ue culture tubes, each tube containing 2 x 10 infected cells in 1.5 ml of medium. Test compounds are dissolved in either aqueous medium or dimethyl sulphoxide, according to solu-bility, and a 15 ~1 solution of the substance added. The 25 cultures are incubated at 37~C for 72 hour6 in a humidi-fied atmosphere containing 5% carbon dioxide in air. The culture6 are then centrifuged and an aliquot of the super-natant solubilized with Nonidet P40 and subjected to an antigen capture assay which uses a primary antiserum with 30 particular reactivity against the viral protein 24 and a hor6eradi6h peroxida6e detection 6y6tem. Colour generation is measured spectrophotometrically and plotted again6t the concentration of te6t 6ub6tance. The concentration that produce6 50% protection i6 determined (I50). *Trademark ~ -A cytotoxicity assay ba6ed on dye uptake and metabol-i6m or radio-labelled amino acid incorporation i6 run ,~,. ", .~ ~.
2030~33 along6ide the above assay in order to determine antiviral selectivity.
The results obtained in the foregoing tests using the compounds of formula I as the test compound are compiled in the following Table.
Table Compound I I50 R Inhibition of Activity HIV Prot ase (uM) against HIV
Sl s2 (nM) ~
Benzyloxycarbonyl ~ 0.024 ~ 0.0027 20 2-Quinolylcarbonyl ~ 0.033 ~ 0.00037 2 The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered enterally such as orally (e.g. in the form of tablets, coated 25 tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally such as intramuscularly or 30 intravenously (e.g. in the form of injection solutions).
For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules the compounds of formula I and their pharmaceutically acceptable acid 35 addition 6alts can be processed with pharmaceutically inert, inorganic or organic excipients. Lactose, maize starch or derivatives thereof, talc, stearic acid or its 2 ~ 3 3 6alts etc can be used, for example, as 6uch excipients for tablet6, dragees and hard gelatine capsules.
Suitable excipients for soft gelatine capsule6 are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyol6 etc.
Suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi--liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, viscosity-increasing substances, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, 25 buffers, coating agent6 or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formula I and their pharmaceutically acceptable acid 30 addition salts can be used in the treatment or prophylaxis of viral infections, particulaely of retroviral infections. The do~age can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral 35 administration there should suffice a daily dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g (e.g. approximately 300 mg per person), divided in - 15 - 20~4~
preferably 1-3 unit doses, which can, for example, be of the same amount. It will, however, be appreciated that the upper limit given above can be exceeded when thifi i8 found to be indicated.
The following Examples illustrate the pre6ent invention.
Example 1 A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L--asparagine in 20 ml of dry tetrahydrofuran was cooled in 15 an ice/6alt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodi-imide were added and the mixture was stirred for 16 hours.
The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium 20 bicarbonate 601ution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/
methanol (9:1) for the elution to give 434 mg of 2-[3(S)--[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-25 -hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro--(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H] ; NMR:
~ (d4 CH30H, 400 MHz):
30 7.33 (5H, m, PhCH20), 7.25 (2H, m), 7.18 (2H, m), 7.09 (lH, m), 5.05 (2H, 8, PhCH20), 4.42 (lH, dd, Asn a J = 7.8, 6.1), 4.22 (lH, m, -CH2C_CH(OH)- J = 10.7, about 4, about 4), 3.85 (lH, m, -CHC_(OH)CH2- J = 8.0, 6.2, about 4), 3.02 (lH, dd, PhC_(H)CHJ = -13.9, about 4), 35 3.02 (lH, dd, leq J = -12.0, small), 2.69 (lH, dd, PhCH(_)CH- J = -13.9, 10.7), 2.63 (lH, dd, -CH(OH)CH(_)N-J = -12-6, 8.0), 2.62 (lH. dd, H3aX J = about 11, 20304~
6mall), 2.57 (lH, dd, A6n Bl J = -15.2, 6.1), 2.38 (lH, dd, A6n ~2 J = -15.2, 7.8), 2.19 (lH, dd, -CH(OH)C_(H)N- J = -12.6, 6.2), 2.17 (lH, dd, 1 J = -12.0, 3.Z), 2.07 (lH, m, H4 J = -12.7, about 11, about 11.5), 1.78 (lH, m, H4a J4a-4ax J = 6mall~ J4 8 = 8mall), 1.63 (lH, m, H8a J8a-lax = 3-2~ J8a_leq = 6mall, J8a 4a = 6mall), 1.35 (lH, m, H4 J = -12.7, 6mall, 6mall), 1.30 (9H, 6, t-butyl), 2.0-1.2 (8H, m).
The 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS,8aS)-i60quinoline-3(S)-carboxamide u6ed a6 the 6tarting material wa6 prepared a6 follow6:
(i) A 6u6pen6ion of 12.676 g (71.6 mmol) of 1,2,3,4-tetra-hydro-3(S)-isoquinolinecarboxylic acid (Chem. Pharm. Bull.
1983, 31, 312) in 200 ml of 90% acetic acid wa6 hydrogen-ated at 80~C and under 140 atmo6phere6 pre66ure over 5%
rhodium-on-carbon for 24 hour6. The mixture wa6 left to cool to room temperature and the cataly6t wa6 then filtered off. The filtrate wa6 evaporated to give a gum which wa6 di6601ved in 10 ml of ethyl acetate and added 610wly to 100 ml of vigorou61y 6tirred dii60propyl ether.
A re6inous precipitate wa6 produced. The 6upernatant liquor6 were removed by decantation and the precipitate wa6 extracted with hot ethyl acetate. Thi6 hot 601ution wa6 poured into a vigorou61y 6tirred mixture of 150 ml of diethyl ether/dii60propyl ether (1:1) to give a pale grey 601id which wa6 collected by filtration, wa6hed with diethyl ether and dried. There were obtained 5.209 g of a mixture of decahydroi60quinoline-3(S)-carboxylic acid6 con6i6ting of predominantly (about 65%) the 4aS,8aS i60mer together with the 4aR,8aR i60mer (about 25%) and about 10%
of the tran6 i60mer6: MS: m/e 184 tM~H] .
(ii) 9.036 g (49.4 mmol) of the foregoing mixture of decahydroi60quinoline-3(S)-carboxylic acid6 were di6601ved 2~3a~
in 50 ml (50 mmol) of lM sodium hydroxide 601ution and the resulting 601ution wa6 cooled to 0~C. 7.40 ml (51.87 mmol) of benzyl chloroformate and 58.7 ml (58.7 mmol) of lM sodium hydroxide solution were added dropwise over a period of 1 hour while maintaining a temperature of 0-5~C by cooling.
The mixture was then stirred for a further 2 hours, during which time the mixture was allowed to warm to room temperature. 100 ml of diethyl ether were added and the mixture wa6 filtered, whereby the insoluble R,R-i60mer was removed. The aqueous layer of the f iltrate was separated and adjusted to pH 1.5-2 by the addition of concentrated hydrochloric acid, whereby an oil precipitated. The mixture was extracted twice with 100 ml of ethyl acetate each time.
The combined organic extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was dissolved in 35 ml of ethyl acetate and 2.85 ml (25 mmol) of cyclohexylamine were added. The white precipitate was collected by filtration to give, after several fractional recrystallizations from methanol/ethyl acetate, 2.38 g of the cyclohexylamine salt of 2-(benzyloxy-carbonyl)-decahydro-(4aS,8aS)-i60quinoline-3(S)-carboxylic acid: MS: m/e 318 [M+H] .
(iii) 2.334 g of the cyclohexylamine salt of 2-(benzyloxy-carbonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid were partitioned between 50 ml of ethyl acetate and 50 ml of 10% citric acid solution. The organic phase was 6eparated, wa6hed with water, filtered and evaporated to give 1.87 g of 2-(benzyloxycarbonyl)-decahydro-(4aS,~aS)--isoquinoline-3(S)-carboxylic acid in the form of a colourless gum; MS: m/e 318 tM+H] .
(iv) A solution of 0.634 g (2.0 mmol) of 2-(benzyloxycar-bonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid in 6 ml of dimethoxyethane was treated with 0.23 g (2.0 mmol) of N-hydroxysuccinimide and 0.412 g (2.0 mmol) of dicyclohexylcarbodiimide. The mixture was stirred at 203~3 room temperature for 18 hours. The mixture was filtered and the filtrate was evaporated to give 0.879 g of the N-hydroxysuccinimide ester of the foregoing acid in the form of a pale yellow oil. A solution of 0.828 g (2.0 mmol) of the foregoing N-hydroxysuccinimide ester in 5 ml of dichloromethane was stirred, cooled to 0~C and treated with 0.219 g (3.0 mmol) of tert.butylamine. The mixture was stirred at 0~C for 2 hours and then at room temperature for 4.5 hours. The mixture wa6 then washed 10 with 2M hydrochloric acid, sodium carbonate solution and sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in 20 ml of diethyl ether and filtered. The filtrate wa6 evaporated to give 0.712 g of 2-(benzyloxycarbonyl)-N-15 -tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide in the form of a white solid; MS: m/e 373 [M+H] .
(v) A solution of 0.689 g (1.85 mmol) of 2-(benzyloxy-carbonyl)-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S) 20 -carboxamide in 20 ml of ethanol was hydrogenated in the presence of 0.01 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 18 hours.
The catalyst was removed by filtration and the solvent was removed by evaporation to give in quantitative yield 25 N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide as a clear oil; MS: m/e 239 tM+H] , which was used in the next step without further purification.
(vi) A solution of 440 mg of N-tert.butyl-decahydro-30 -(4aS,8aS)-isoquinoline-3(S)-carboxamide and 549 mg of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 6 ml of ethanol was stirred at 60~C for 7 hours. A further 54 mg of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenyl-butane were added and the solution was stirred at 20~C for 35 16 hours. The solvent wa6 removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/n-hexane/methanol (47.5:47.5:5) for the elution to 2~30433 give 771 mg of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy--4-phenylbutyl-N-tert.butyl-decahydro-(4aS,8aS)-isoquino-line-3(S)-carboxamide as a white solid; MS: m/e 536 [M+H] .
(vii) A solution of 747 mg of 2-[3(S)-(benzyloxyform-amido)-2(R)-hydroxy-4-phenylbutyl-N-tert.butyl-deca-hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 40 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 10 20~C and under atmo8pheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 561 mg of Z-[3(S)-amino-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a buff coloured solid which was used in the next step without further purification.
Example 2 A solution of 154 mg of 2-[3(S)-t(L-asparaginyl)-amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro--(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was coold in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide 25 were added and the mixture was 6tirred for 64 hours. The mixture wa6 diluted with ethyl acetate and filtered. The filtrate wa6 washed with aqueous 60dium bicarbonate solution and with sodium chloride solution and then evaporated. The residue wa6 chromatographed on 6ilica gel 30 u6ing dichloromethane/ methanol (9:1) for the elution to give 50 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4--phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H] ; NMR: ~ (d4 CH30H, 400 MHz):
~o~a4~
8.52 (lH, m), 8.18 (lH, m), 8.14 (lH, m), 8.02 (lH, m), 7.84 (lH, m), 7.69 (lH, m), 7.18 (2H, m), 6.90 (2H, m), 6.72 (lH, m), 4.93 (lH, dd, Asn aCH J = 6.6, 6.8), 4.27 (lH, m, -CH2CHCH(OH)- J = 3.8, 3.8, 11.0), 3.89 (lH, m, -CHCH(OH)CH2- J = 7.2, 6.4, 3.8), 3.06 (lH, dd, Hl J = -12.0, 3.0), 3.02 (lH, dd, PhCH(H)CH- J = -14.0, 3.8), 2.77 (lH, dd, A6n ~1 J = -15.6, 6.6), 2.68 (lH, dd, Asn B2 J = -15.6, 6.8), 2.68 (lH, dd, PhCH(_)CH- J = -14.0, 11.0), about 2.68 (lH, dd, -CH(OH)CH(H)N- J = -12.0, 7.2), 10 2-63 (lH, dd, H3aX J = 11.0, 2.2), 2.22 (lH, dd, -CH(OH)CH(H)N- J = -12.0, 6.4), 2.18 (lH, dd, Hl J = -12.0, 2.2), 2.06 (lH, m, H4 J = -11.0, 11.0, 11 o) 1.78 (lH. m, 4a J4a 4ax = 11-0- 4a-4eq 4' J4 8a = about 4), 1.65 (lH, m, 8a J8 1 = 2.2 15 J8 1 = 3 0 J8 4 = about 4), 1.37 (lH, m, H4eq J = -11.0, 2.2, about 4), 1.30 (9H, s, t-butyl), 2.0-1.2 (8H, m).
The 2-[3(S)-t(L-asparaginyl)amino]-2(R)-hydroxy-4-20 -phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline--3(S)-carboxamide u~ed as the starting material was prepared as follows:
A solution of 195 mg of 2-[3(S)-[[N-(benzyloxycar-25 bonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N--tert.butyl-decahydro-(4aS,8aS)-i60quinoline-3(S)-carbox-amide in 20 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for 18 hour~ over 10 mg of 10% palladium-on-charcoal. The catalyst was 30 filtered off and the filtrate was evaporated under reduced pres6ure to give 154 mg of 2-[3(S)-[(L-asparaginyl)amino]--2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro--(4aS,8aS)-i~oquinoline-3(S)-carboxamide which was u~ed in the next ~tep without further purification.
~3~3 Example 3 A solution of 287 mg of N-(2-quinolylcarbonyl)-L--asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline--3(S)-carboxamide [prepared as described in Example 1 (i)-(vii)] in 3 ml of tetrahydrofuran was cooled to -10~C
and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture 10 wa8 8tirred at -10~C for 2 hours and at 20~C for 16 hour6, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated.
The residue wa6 chromatographed on silica gel u6ing 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4--phenyl-3(S)-t[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide which was identical with the product obtained in the first para-20 graph of Example 2.
The N-(2-quinolylcarbonyl)-L-asparagine used a6 the starting material was prepared as follows:
A mixture of 540 mg of quinaldic acid succinamide ester and 300 mg of L-asparagine monohydrate in 2 ml of dimethylformamide was stirred at 20~C for 96 hours. The solvent was removed by evaporation to give a white solid residue which was stirred vigorously in 10 ml of dichloro-30 methane, filtered off and washed with dichloromethane.There were thus obtained 431 mg of N-(2-quinolylcarbonyl)--L-asparagine as a white solid; MS: m/e 288tM+H]+.
The following Example illustrates the manufacture of a 35 pharmaceutical preparation containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof as the active ingredient:
- 22 - 2~3~3 ExamPle A
An aqueous solution of the acti~e ingredient is filtered sterile and mixed while warming with a sterile gelatine solution, which contain6 phenol as a preserving agent, using amounts such that 1.00 ml of the resulting solution contains 3.0 mg of active ingredient, 150.0 mg of gelatine, 4.7 mg of phenol and distilled water ad 1.0 ml.
The mixture is filled into vials of 1.0 ml capacity under 10 aseptic conditions.
The present invention is concerned with amino acid derivatives.
The amino acid derivatives provided by the present invention are compounds of the general formula ~ ~ ~
NH2 NHC(CH3)3 wherein R represents benzyloxycarbonyl or 2-quinolylcarbonyl, and pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I and their pharmaceutically acceptable acid addition salts are novel and possess valuable pharmacological properties. In particular, they inhibit proteases of viral origin and can be used in the prophylaxi6 or treatment of viral infections, particularly of infections caused by HIV and other retroid viruses.
Objects of the present invention are the compounds of Kbr/30.8.90 2~3~433 formula I and their aforementioned salts per se and for use as therapeutically active substance6, a process for the manufacture of said compounds and salts, intermediates used in said process, medicaments containing said compounds and salts, the use of said compounds and salts in the control or prevention of illnesses, especially in the treatment or prophylaxis of viral infections, and the use of said compounds and salts for the manufacture of medicaments for the treatment or prophylaxis of viral infections.
The pharmaceutically acceptable acid addition salts of the compounds of formula I are salts formed with inorganic acids, for example hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc, or with organic acids, for example acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid etc.
According to the process provided by the present invention, the compounds of formula I hereinbefore and their pharmaceutically acceptable acid addition salt6 are manufactured by (a) reacting 2-[(3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N--tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide of the formula 2 03~43~
~ ) H2N ~ ~ II
o NHC(CH3)3 with an acid of the general formula H ¦¦
~ N ~ C OH
20 ~ III
'ro ;~H2 wherein R has the fiignificance given earlier, or a reactive derivative thereof, or (b) reducing a compound of the general formula - 4 - ~3'Q4~3 o r~
~H~ IV
~ro ~
NH2 NHC(CH3)3 wherein R has the significance given earlier, and separating the desired 2(R)-hydroxy isomer from the mixture obtained, or (c) reacting 2-t3(S)-r(L-asparaginyl)amino]-2(R)-hydroxy--4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-iso-quinoline-3(S)-carboxamide of the formula 2S ~
H2N~ ~ V
'r~ ~
NH2 ~ ~tHC(CH3)3 with an agent yielding the benzyloxycarbonyl or 20~0~3~
2-quinolylcarbonyl group, and (d) if desired, converting a compound of formula I
obtained into a pharmaceutically acceptable acid addition salt.
The reaction of a compound of formula II with an acid of formula III in accordance with embodiment (a) of the process can be carried out in accordance with method6 known per se in peptide chemistry. Thus, when an acid of formula III is used, the reaction is preferably carried out in the presence of a condensation agent such as hydroxybenzotriazole and dicyclohexylcarbodiimide. Thi6 reaction is conveniently carried out in an inert organic solvent such as an ether (e.g. diethyl ether, tetrahydro-furan etc) or dimethylformamide at a low temperature, suitably at about -10~C to +5~C and especially at about 0~C. Suitable reactive derivatives of acids of formula III
which can be used are, for example, the corresponding acid halide6 (e.g. acid chlorides), acid anhydrides, mixed anhydrides, activated ester6 etc. When a reactive derivative is used, the reaction is conveniently carried out in an inert organic solvent such as a halogenated aliphatic hydrocarbon (e.g. dichloromethane etc) or an ether (e.g. diethyl ether, tetrahydrofuran etc) and, where appropriate, in the presence or an organic base (e.g.
N-ethylmorpholine, diisopropylethylamine etc) at a low temperature, suitably at about -10~C to +5~C and especially at about 0~C.
The reduction of a compound of formula IV in accordance with embodiment (b) of the proces6 can be carried out according to methods known per se for the reduction of a carbonyl group to a hydroxy group. Thus, 35 for example, the reduction can be carried out using a complex metal hydride such as an alkali metal borohydride, - 6 - 2D3 ~33 especially sodium borohydride, in an appropriate organic solvent ~uch as an alkanol (e.g. methanol, ethanol, propanol, isopropanol etc). Conveniently, the reduction is carried out at about room temperature. The separation of the desired 2(R)-hydroxy isomer from the mixture obtained can be performed according to conventional methods, e.g.
by chromatography and the like.
In accordance with embodiment (c) of the process, the suitable agent yielding the benzyloxycarbonyl group is benzyl chloroformate. Suitable agent~ which yield the 2-quinolylcarbonyl group are the corre~ponding acid or reactive derivatives thereof such as the corresponding acid halides (e.g. acid chloride), acid anhydride, mixed anhydrides, activated e~ters etc. The reaction of a compound of formula V with the aforementioned agents i~
carried out in the same manner as that described earlier in connection with embodiment (a) of the process.
The conversion of a compound of formula I into a pharmaceutically acceptable acid addition salt in accordance with embodiment (d) of the proce6s can be carried out by treating ~uch a compound in a conventional manner with an inorganic acid, for example a hydrohalic 25 acid 6uch as hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc, or with an organic acid such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methane6ulphonic acid, p-toluenesulphonic acid etc.
The compound of formula II which i6 used as 6tarting material in embodiment (a) of the process is novel and also forms an object of the present invention.
The compound of f ormula II can be prepared, f or example, by reacting a compound of the general formula ~D3a~33 V~
~N~--X
o 10 wherein Rl represents a amino-protecting group (e.g.
tert.butoxycarbonyl or benzyloxyca~bonyl) and X
represents a chlorine or bromine atom, with N-tert.butyl-decahydro-(4aS,8aS)isoquinoline-3(5)--carboxamide of the formula HN/~
o, ~J VII
NHC(CH3) 3 and reducing the resulting compound of the general formula H~-- ~ ~ I I I
o~b~
NHC(CH3)3 203Q~33 wherein R has the significance given earlier, ~eparating the desired 2(R)-hydroxy isomer from the mixture obtained and cleaving off the group R from the S resulting compound of the general formula ~
0~ ~ IX
0~
N~C(C~3)3 wherein R has the significance given earlier, to give a compound of formula II.
The reaction of a compound of formula VI, preferably one in which Rl represents benzyloxycarbonyl, with a compound of formula VII can be carried out in a known manner; for example, in an inert organic ~olvent such a6 a halogenated aliphatic hydrocarbon (e.g. dichloromethane etc) and in the presence of a ba~e (e.g. a tcialkylamine such a~ triethylamine etc), conveniently at about room temperature.
The reduction of a compound of formula VIII to give a compound of formula IX and the sub~equent separation of the desired 2(R)-hydroxy isomer can be carried out as described earlier in connection with embodiment (b) of the process of the invention, i.e. the reduction of a compound of formula IV and the separation of the desired 2(R)--hydroxy isomer from the mixture obtained.
The cleavage of the group Rl from a compound of formula IX can al~o be carried out in a known manner; for example, using a strong inorganic acid such as a hydrohalic acid or a strong organic acid (e.g. trifluoro-acetic acid etc), conveniently at about 0~C to about room temperature. Alternatively, a hydrogenolytically-cleavable amino-protecting group R can be cleaved off using hydrogen in the presence of a noble-metal catalyst (e.g. a palladium catalyst such as palladium-on-carbon) in an organic solvent or solvent mixture which is inert under the reaction conditions (e.g. an alkanol such as ethanol, isopropanol etc, an alkanecarboxylic acid ester such as ethyl acetate, etc) and conveniently at about room temperature.
A further method for the preparation of the compound of formula II comprises firstly reacting a compound of the general formula ~ ~ X
~N~
wherein R has the significance given earlier, with the compound of formula VII hereinbefore, conveniently in an inert organic solvent such as an alkanol (e.g. methanol etc), dimethylformamide or the like 35 and at an elevated temperature, conveniently at about 600C
to about 120~C, and then cleaving off the group R in the reaction product (a compound of formula IX
2 ~ 3 hereinbefore) as described earlier.
The compounds of formula IV which are used as starting materials in embodiment (b) of the process can be prepared, for example, by cleaving off the amino--protecting group R from a compound of formula VIII and reacting the product with an acid of formula III or a reactive derivative thereof. This reaction can be carried out in an analogous manner to that described earlier in connection with embodiment (a) of the process.
The compound of formula V which is used as starting material in embodiments (c) of the process is novel and forms a further object of the present invention.
The compound of formula V can be prepared, for example, by cleaving off the benzyloxycarbonyl group R
from the compound of formula I in which R represents benzyloxycarbonyl or the tert.butoxycarbonyl group form a 20 compound corresponding to formula I but in which R
represents tert.butoxycarbonyl. This latter compound can be prepared, for example, by reacting the compound of formula II with N-(tert.butoxycarbonyl)-L-asparagine in accordance with embodiment (a) of the process. The above 25 cleavage is carried out in a manner analogous to that described earlier in connection with the cleavage of the group R from a compound of formula VIII.
The starting materials of formula III and their 30 reactive derivatives as well as the compounds of formulae VI, VII and X hereinbefore, insofar as they are not known compounds or analogues of known compounds, can be prepared in a similar manner to the known compounds or as described in the Examples hereinafter or in analogy thereto.
35 Moreover, the agents used in embodiment (c) of the process are generally known compounds.
f~
--- 2D3~}33 As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and are useful in the treatment or prophylaxis of viral infections, particularly of infections caused by HIV and other retroid viruses.
The in vitro inhibition of HIV protease by the compounds provided by the present invention can be demonstrated by means of the following test:
HIV protease was expressed in E. coli and partially purified from soluble extracts of the bacterium by ammonium sulphate fractionation (0-30%). Protease activity was assayed using the protected hexapeptide succinyl-Ser--Leu-Asn-Tyr-Pro-Ile isobutylamide (S ) or the protected heptapeptide succinyl-Val-Ser-Gln-Asn-Phe-Pro-Ile isobutylamide (S ) as the substrate. Cleavage of the substrate was quantified by measuring the production of H-Pro-Ile isobutylamide by the spectrophotometric assay of 20 N-terminal proline.
1.25 mM of substrate were dissolved in 125 mM of citrate buffer (pH 5.5) containing 0.125 mg/ml of Tween 20. 10 ~1 of a solution of various concentrations 25 of the test compound (dissolved in methanol or dimethyl sulphoxide and diluted with water containing 0.1%
Tween 20) and 10 ~1 of protease were added to 80 ~1 of the above buffered substrate. Digestion was carried out at 37~C for a fixed period of time and was terminated by the 30 addition of 1 ml of colour reagent r30 ~g/ml of isatin and 1.5 mg/ml of 2-(4-chlorobenzoyl)benzoic acid in 10%
acetone in ethanol (vol./vol.)]. The solution was heated in a water bath and then the pigmented residues were re-dissolved in 1 ml of 1% pyrogallol in 33% water in - -3S acetone (wt./vol./vol.). The optical density of the ~olution was measured spectrophotometrically at 599 nm.
The formation of H-Pro-Ile isobutylamide in the presence *Trademark ~i -- 2O3OL~ 33 of the te6t compound was compared with controls and the concentration of te6t compound required to give 50%
inhibition (I50) wa6 determined by mean6 of a graph plotted from the variou6 concentrations of test compound used.
The in vitro antiviral activity of the compounds of formula I can be demonstrated in the assay described below:
Activity aqainst HIV:
This assay uses HTLV-III (6train RF) grown in C8166 cell6 (a human CD4 T lymphoblastoid line) using RPMl 1640 medium with bicarbonate buffer, antibiotics and 10%
15 foetal bovine serum.
A suspension of cells is infected with ten times the TCD50 ~f virus and ad60rption allowed to proceed for 90 minute6 at 37~C. The cells are washed three times with 20 medium. The test is carried out in 6 ml tis6ue culture tubes, each tube containing 2 x 10 infected cells in 1.5 ml of medium. Test compounds are dissolved in either aqueous medium or dimethyl sulphoxide, according to solu-bility, and a 15 ~1 solution of the substance added. The 25 cultures are incubated at 37~C for 72 hour6 in a humidi-fied atmosphere containing 5% carbon dioxide in air. The culture6 are then centrifuged and an aliquot of the super-natant solubilized with Nonidet P40 and subjected to an antigen capture assay which uses a primary antiserum with 30 particular reactivity against the viral protein 24 and a hor6eradi6h peroxida6e detection 6y6tem. Colour generation is measured spectrophotometrically and plotted again6t the concentration of te6t 6ub6tance. The concentration that produce6 50% protection i6 determined (I50). *Trademark ~ -A cytotoxicity assay ba6ed on dye uptake and metabol-i6m or radio-labelled amino acid incorporation i6 run ,~,. ", .~ ~.
2030~33 along6ide the above assay in order to determine antiviral selectivity.
The results obtained in the foregoing tests using the compounds of formula I as the test compound are compiled in the following Table.
Table Compound I I50 R Inhibition of Activity HIV Prot ase (uM) against HIV
Sl s2 (nM) ~
Benzyloxycarbonyl ~ 0.024 ~ 0.0027 20 2-Quinolylcarbonyl ~ 0.033 ~ 0.00037 2 The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered enterally such as orally (e.g. in the form of tablets, coated 25 tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally such as intramuscularly or 30 intravenously (e.g. in the form of injection solutions).
For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules the compounds of formula I and their pharmaceutically acceptable acid 35 addition 6alts can be processed with pharmaceutically inert, inorganic or organic excipients. Lactose, maize starch or derivatives thereof, talc, stearic acid or its 2 ~ 3 3 6alts etc can be used, for example, as 6uch excipients for tablet6, dragees and hard gelatine capsules.
Suitable excipients for soft gelatine capsule6 are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyol6 etc.
Suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi--liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, viscosity-increasing substances, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, 25 buffers, coating agent6 or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formula I and their pharmaceutically acceptable acid 30 addition salts can be used in the treatment or prophylaxis of viral infections, particulaely of retroviral infections. The do~age can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral 35 administration there should suffice a daily dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g (e.g. approximately 300 mg per person), divided in - 15 - 20~4~
preferably 1-3 unit doses, which can, for example, be of the same amount. It will, however, be appreciated that the upper limit given above can be exceeded when thifi i8 found to be indicated.
The following Examples illustrate the pre6ent invention.
Example 1 A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L--asparagine in 20 ml of dry tetrahydrofuran was cooled in 15 an ice/6alt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodi-imide were added and the mixture was stirred for 16 hours.
The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium 20 bicarbonate 601ution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/
methanol (9:1) for the elution to give 434 mg of 2-[3(S)--[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-25 -hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro--(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H] ; NMR:
~ (d4 CH30H, 400 MHz):
30 7.33 (5H, m, PhCH20), 7.25 (2H, m), 7.18 (2H, m), 7.09 (lH, m), 5.05 (2H, 8, PhCH20), 4.42 (lH, dd, Asn a J = 7.8, 6.1), 4.22 (lH, m, -CH2C_CH(OH)- J = 10.7, about 4, about 4), 3.85 (lH, m, -CHC_(OH)CH2- J = 8.0, 6.2, about 4), 3.02 (lH, dd, PhC_(H)CHJ = -13.9, about 4), 35 3.02 (lH, dd, leq J = -12.0, small), 2.69 (lH, dd, PhCH(_)CH- J = -13.9, 10.7), 2.63 (lH, dd, -CH(OH)CH(_)N-J = -12-6, 8.0), 2.62 (lH. dd, H3aX J = about 11, 20304~
6mall), 2.57 (lH, dd, A6n Bl J = -15.2, 6.1), 2.38 (lH, dd, A6n ~2 J = -15.2, 7.8), 2.19 (lH, dd, -CH(OH)C_(H)N- J = -12.6, 6.2), 2.17 (lH, dd, 1 J = -12.0, 3.Z), 2.07 (lH, m, H4 J = -12.7, about 11, about 11.5), 1.78 (lH, m, H4a J4a-4ax J = 6mall~ J4 8 = 8mall), 1.63 (lH, m, H8a J8a-lax = 3-2~ J8a_leq = 6mall, J8a 4a = 6mall), 1.35 (lH, m, H4 J = -12.7, 6mall, 6mall), 1.30 (9H, 6, t-butyl), 2.0-1.2 (8H, m).
The 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS,8aS)-i60quinoline-3(S)-carboxamide u6ed a6 the 6tarting material wa6 prepared a6 follow6:
(i) A 6u6pen6ion of 12.676 g (71.6 mmol) of 1,2,3,4-tetra-hydro-3(S)-isoquinolinecarboxylic acid (Chem. Pharm. Bull.
1983, 31, 312) in 200 ml of 90% acetic acid wa6 hydrogen-ated at 80~C and under 140 atmo6phere6 pre66ure over 5%
rhodium-on-carbon for 24 hour6. The mixture wa6 left to cool to room temperature and the cataly6t wa6 then filtered off. The filtrate wa6 evaporated to give a gum which wa6 di6601ved in 10 ml of ethyl acetate and added 610wly to 100 ml of vigorou61y 6tirred dii60propyl ether.
A re6inous precipitate wa6 produced. The 6upernatant liquor6 were removed by decantation and the precipitate wa6 extracted with hot ethyl acetate. Thi6 hot 601ution wa6 poured into a vigorou61y 6tirred mixture of 150 ml of diethyl ether/dii60propyl ether (1:1) to give a pale grey 601id which wa6 collected by filtration, wa6hed with diethyl ether and dried. There were obtained 5.209 g of a mixture of decahydroi60quinoline-3(S)-carboxylic acid6 con6i6ting of predominantly (about 65%) the 4aS,8aS i60mer together with the 4aR,8aR i60mer (about 25%) and about 10%
of the tran6 i60mer6: MS: m/e 184 tM~H] .
(ii) 9.036 g (49.4 mmol) of the foregoing mixture of decahydroi60quinoline-3(S)-carboxylic acid6 were di6601ved 2~3a~
in 50 ml (50 mmol) of lM sodium hydroxide 601ution and the resulting 601ution wa6 cooled to 0~C. 7.40 ml (51.87 mmol) of benzyl chloroformate and 58.7 ml (58.7 mmol) of lM sodium hydroxide solution were added dropwise over a period of 1 hour while maintaining a temperature of 0-5~C by cooling.
The mixture was then stirred for a further 2 hours, during which time the mixture was allowed to warm to room temperature. 100 ml of diethyl ether were added and the mixture wa6 filtered, whereby the insoluble R,R-i60mer was removed. The aqueous layer of the f iltrate was separated and adjusted to pH 1.5-2 by the addition of concentrated hydrochloric acid, whereby an oil precipitated. The mixture was extracted twice with 100 ml of ethyl acetate each time.
The combined organic extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was dissolved in 35 ml of ethyl acetate and 2.85 ml (25 mmol) of cyclohexylamine were added. The white precipitate was collected by filtration to give, after several fractional recrystallizations from methanol/ethyl acetate, 2.38 g of the cyclohexylamine salt of 2-(benzyloxy-carbonyl)-decahydro-(4aS,8aS)-i60quinoline-3(S)-carboxylic acid: MS: m/e 318 [M+H] .
(iii) 2.334 g of the cyclohexylamine salt of 2-(benzyloxy-carbonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid were partitioned between 50 ml of ethyl acetate and 50 ml of 10% citric acid solution. The organic phase was 6eparated, wa6hed with water, filtered and evaporated to give 1.87 g of 2-(benzyloxycarbonyl)-decahydro-(4aS,~aS)--isoquinoline-3(S)-carboxylic acid in the form of a colourless gum; MS: m/e 318 tM+H] .
(iv) A solution of 0.634 g (2.0 mmol) of 2-(benzyloxycar-bonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid in 6 ml of dimethoxyethane was treated with 0.23 g (2.0 mmol) of N-hydroxysuccinimide and 0.412 g (2.0 mmol) of dicyclohexylcarbodiimide. The mixture was stirred at 203~3 room temperature for 18 hours. The mixture was filtered and the filtrate was evaporated to give 0.879 g of the N-hydroxysuccinimide ester of the foregoing acid in the form of a pale yellow oil. A solution of 0.828 g (2.0 mmol) of the foregoing N-hydroxysuccinimide ester in 5 ml of dichloromethane was stirred, cooled to 0~C and treated with 0.219 g (3.0 mmol) of tert.butylamine. The mixture was stirred at 0~C for 2 hours and then at room temperature for 4.5 hours. The mixture wa6 then washed 10 with 2M hydrochloric acid, sodium carbonate solution and sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in 20 ml of diethyl ether and filtered. The filtrate wa6 evaporated to give 0.712 g of 2-(benzyloxycarbonyl)-N-15 -tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide in the form of a white solid; MS: m/e 373 [M+H] .
(v) A solution of 0.689 g (1.85 mmol) of 2-(benzyloxy-carbonyl)-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S) 20 -carboxamide in 20 ml of ethanol was hydrogenated in the presence of 0.01 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 18 hours.
The catalyst was removed by filtration and the solvent was removed by evaporation to give in quantitative yield 25 N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide as a clear oil; MS: m/e 239 tM+H] , which was used in the next step without further purification.
(vi) A solution of 440 mg of N-tert.butyl-decahydro-30 -(4aS,8aS)-isoquinoline-3(S)-carboxamide and 549 mg of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 6 ml of ethanol was stirred at 60~C for 7 hours. A further 54 mg of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenyl-butane were added and the solution was stirred at 20~C for 35 16 hours. The solvent wa6 removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/n-hexane/methanol (47.5:47.5:5) for the elution to 2~30433 give 771 mg of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy--4-phenylbutyl-N-tert.butyl-decahydro-(4aS,8aS)-isoquino-line-3(S)-carboxamide as a white solid; MS: m/e 536 [M+H] .
(vii) A solution of 747 mg of 2-[3(S)-(benzyloxyform-amido)-2(R)-hydroxy-4-phenylbutyl-N-tert.butyl-deca-hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 40 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 10 20~C and under atmo8pheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 561 mg of Z-[3(S)-amino-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a buff coloured solid which was used in the next step without further purification.
Example 2 A solution of 154 mg of 2-[3(S)-t(L-asparaginyl)-amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro--(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was coold in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide 25 were added and the mixture was 6tirred for 64 hours. The mixture wa6 diluted with ethyl acetate and filtered. The filtrate wa6 washed with aqueous 60dium bicarbonate solution and with sodium chloride solution and then evaporated. The residue wa6 chromatographed on 6ilica gel 30 u6ing dichloromethane/ methanol (9:1) for the elution to give 50 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4--phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H] ; NMR: ~ (d4 CH30H, 400 MHz):
~o~a4~
8.52 (lH, m), 8.18 (lH, m), 8.14 (lH, m), 8.02 (lH, m), 7.84 (lH, m), 7.69 (lH, m), 7.18 (2H, m), 6.90 (2H, m), 6.72 (lH, m), 4.93 (lH, dd, Asn aCH J = 6.6, 6.8), 4.27 (lH, m, -CH2CHCH(OH)- J = 3.8, 3.8, 11.0), 3.89 (lH, m, -CHCH(OH)CH2- J = 7.2, 6.4, 3.8), 3.06 (lH, dd, Hl J = -12.0, 3.0), 3.02 (lH, dd, PhCH(H)CH- J = -14.0, 3.8), 2.77 (lH, dd, A6n ~1 J = -15.6, 6.6), 2.68 (lH, dd, Asn B2 J = -15.6, 6.8), 2.68 (lH, dd, PhCH(_)CH- J = -14.0, 11.0), about 2.68 (lH, dd, -CH(OH)CH(H)N- J = -12.0, 7.2), 10 2-63 (lH, dd, H3aX J = 11.0, 2.2), 2.22 (lH, dd, -CH(OH)CH(H)N- J = -12.0, 6.4), 2.18 (lH, dd, Hl J = -12.0, 2.2), 2.06 (lH, m, H4 J = -11.0, 11.0, 11 o) 1.78 (lH. m, 4a J4a 4ax = 11-0- 4a-4eq 4' J4 8a = about 4), 1.65 (lH, m, 8a J8 1 = 2.2 15 J8 1 = 3 0 J8 4 = about 4), 1.37 (lH, m, H4eq J = -11.0, 2.2, about 4), 1.30 (9H, s, t-butyl), 2.0-1.2 (8H, m).
The 2-[3(S)-t(L-asparaginyl)amino]-2(R)-hydroxy-4-20 -phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline--3(S)-carboxamide u~ed as the starting material was prepared as follows:
A solution of 195 mg of 2-[3(S)-[[N-(benzyloxycar-25 bonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N--tert.butyl-decahydro-(4aS,8aS)-i60quinoline-3(S)-carbox-amide in 20 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for 18 hour~ over 10 mg of 10% palladium-on-charcoal. The catalyst was 30 filtered off and the filtrate was evaporated under reduced pres6ure to give 154 mg of 2-[3(S)-[(L-asparaginyl)amino]--2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro--(4aS,8aS)-i~oquinoline-3(S)-carboxamide which was u~ed in the next ~tep without further purification.
~3~3 Example 3 A solution of 287 mg of N-(2-quinolylcarbonyl)-L--asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline--3(S)-carboxamide [prepared as described in Example 1 (i)-(vii)] in 3 ml of tetrahydrofuran was cooled to -10~C
and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture 10 wa8 8tirred at -10~C for 2 hours and at 20~C for 16 hour6, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated.
The residue wa6 chromatographed on silica gel u6ing 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4--phenyl-3(S)-t[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide which was identical with the product obtained in the first para-20 graph of Example 2.
The N-(2-quinolylcarbonyl)-L-asparagine used a6 the starting material was prepared as follows:
A mixture of 540 mg of quinaldic acid succinamide ester and 300 mg of L-asparagine monohydrate in 2 ml of dimethylformamide was stirred at 20~C for 96 hours. The solvent was removed by evaporation to give a white solid residue which was stirred vigorously in 10 ml of dichloro-30 methane, filtered off and washed with dichloromethane.There were thus obtained 431 mg of N-(2-quinolylcarbonyl)--L-asparagine as a white solid; MS: m/e 288tM+H]+.
The following Example illustrates the manufacture of a 35 pharmaceutical preparation containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof as the active ingredient:
- 22 - 2~3~3 ExamPle A
An aqueous solution of the acti~e ingredient is filtered sterile and mixed while warming with a sterile gelatine solution, which contain6 phenol as a preserving agent, using amounts such that 1.00 ml of the resulting solution contains 3.0 mg of active ingredient, 150.0 mg of gelatine, 4.7 mg of phenol and distilled water ad 1.0 ml.
The mixture is filled into vials of 1.0 ml capacity under 10 aseptic conditions.
Claims (9)
1. Amino acid derivatives of the general formula wherein R represents benzyloxycarbonyl or
2-quinolylcarbonyl, and pharmaceutically acceptable acid addition salts thereof.
2. N-tert.Butyl-decahydro-2-[2(R)-hydroxy-4-phenyl--3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]--(4aS,8aS)-isoquinoline-3(S)-carboxamide.
2. N-tert.Butyl-decahydro-2-[2(R)-hydroxy-4-phenyl--3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]--(4aS,8aS)-isoquinoline-3(S)-carboxamide.
3. 2-[3(S)-Amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ,
4. 2-[3(S)-[(L-Asparaginyl)amino]-2(R)-hydroxy-4--phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula
5. An amino acid derivative according to claim 1 or claim 2 for use in the treatment or prophylaxis of viral infections.
6. A process for the manufacture of an amino acid derivative in accordance with claim 1 or claim 2, which process comprises (a) reacting 2-[(3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N--tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carbox-amide of the formula with an acid of the general formula wherein R ac defined in claim 1, or a reactive derivative thereof, or (b) reducing a compound of the general formula wherein R as defined in claim 1, and separating the desired 2(R)-hydroxy isomer from the mixture obtained, or (c) reacting 2-[3(S)-t(L-asparaginyl)amino]-2(R)-hydroxy--4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-iso-quinoline-3(S)-carboxamide of the formula with an agent yielding the benzyloxycarbonyl or 2-quinolylcarbonyl group, and (d) if desired, converting a compound of formula I
obtained into a pharmaceutically acceptable acid addition salt.
obtained into a pharmaceutically acceptable acid addition salt.
7. A medicament for the treatment or prophylaxis of viral infections, containing an amino acid d-erivative according to claim 1 or claim Z and a therapeutically inert excipient.
8. The use of an amino acid derivative according to claim 1 or claim 2 in the treatment or prophylaxis of viral infections.
9. The use of an amino acid derivative according to claim 1 or claim 2 for the manufacture of a medicament for the treatment or prophylaxis of viral infections.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898927913A GB8927913D0 (en) | 1989-12-11 | 1989-12-11 | Amino acid derivatives |
| GB8927913.7 | 1989-12-11 | ||
| SG120493A SG120493G (en) | 1989-12-11 | 1993-11-02 | N-tert-Butyl-decahydro-2(3-amino-2-hydroxy-4-phenyl-butyl) isoquinoline-3-carboxamide and asparaginyl derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2030433A1 CA2030433A1 (en) | 1991-06-12 |
| CA2030433C true CA2030433C (en) | 1997-10-21 |
Family
ID=26296345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002030433A Expired - Lifetime CA2030433C (en) | 1989-12-11 | 1990-11-21 | New isoquinoline- carboxamide amino acid derivatives useful for treatment of viral diseases |
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