CA1158251A

CA1158251A - 5'-aminoalkyl-4',4,8-trialkylpsoralens

Info

Publication number: CA1158251A
Application number: CA000382640A
Authority: CA
Inventors: Kurt D. Kaufman
Original assignee: Elder Pharmaceuticals Inc
Current assignee: Elder Pharmaceuticals Inc
Priority date: 1980-07-29
Filing date: 1981-07-28
Publication date: 1983-12-06
Also published as: GB2080806B; JPS5753490A; FR2495154A1; DE3129750A1; FR2495154B1; JPS621952B2; GB2080806A; US4294822A

Abstract

APPLICATION FOR
LETTERS PATENT
FOR
5'-AMINOALRYL-4',4,8-TRIALKYLPSORALENS
ABSTRACT OF THE DISCLOSURE
The invention relates to 5'-aminoalkyl-4',4,8-trialkyl-psoralens having enhanced photosensitizing activity, especially oral and topical activity, as well as low toxicity, when com-pared with psoralens of different structure.

INVENTOR: Rurt D. Kaufman 2205 Benjamin Ave.
Kalamazoo, Michigan 49008

Description

~5~25~ ~ ~.nER g BACKGROUND F INVENTION

Field of Invention . . .
Psoralens, photochemotherapy, psoralens having enhanced photosensitizing activity for use in photochemoth~rapy.
Prior Art Psoralens have been used for years as dermal photosensitiz-ing agents, e.g., in the treatment o~ vitiligo. Their topical and/or oral application, followed hy irradiation with li~htr results in stimulation of melanin, thus producing a tanning effect. They have accordingly also been usea for such cosmetic purpose. More recently, psoralens have ~een found useful in the photochemotherapeutic treatment of psoriasis, in which case -they are administered orally or tOpically to the subject, whose skin is subsequently exposed to controlled ultraviolet radiation, as in a Psoralite (TM) apparatus. A high percentage of remissions of this disease have been effected in such manner.
The effectiveness o a psoralen for such uses an~ for such purpD~eis at least partially related bo-its ability bo produce erythe~a upon the skin upon irradiation. Psoralens also have ot~er uses, and their uses,as well as unaerlying rati~nale and theory, are partially ~ucidated in U.S. Patent 4,124,598, and are otherwise well-known in the art from various preexist ing publications.
With the increasing emphasis on photochemotherapeutic treatments for various purposes using psoralens and controlled -application of ultraviolet light, the re~uirements for optimally~effective photosensitizing psoralens have become more apparent. To eliminate -the necessity of excessive ana perhaps dangerous ultraviolet light applications or dosages, '~

1~58~51 TC ELDE~ 9 maximum photosensitization is one obvious criterion. However, to eliminate excessive periods of waiting before photochemo-therapy can be commenced, rapid onset of photos~nsitization upon topical or oral administration of the photosensitizing agent is also of significance. Long or extended action is another criterion of significance in some cases, as when irradiation cannot be applied without some period of delay.
Thus, the criteria of rapid onset, early maximization, and extended period of photosensitization action or effect are lU established as desirable criteria for the photosensitizing agent in this relatively new but rapidly-expanding field of photochemotherapy, certainly of equal importance as contrasted to the single previously-important criterion of high maximum photosensitization activity alone.
The recently-developed 41-aminomethyl-4,5',8-trimethyl-psoralen appears to be characterized by a high order of oral photosensitizing activity, but exhibits a high degree of toxicity.
A low toxicity is, of course, essential. The c~unds 5'-amino-methyl-4'-methylpsoralen and 8-aminomethylpsoralen, on the other hand, are essentially ery~hemically inactive orally, apparently due to absence of the 4-methyl group, thus making the photosensitizing activity even more unpredictable than ever in the area and immediate vicinity of the present invention.
OBJECTS OF THE INVENTION
It is an object of the invention to provide novel psoralen compounds. It is a further object to provide novel psoralen compounds which have enhanced characteristics when compared with psoralen compounds of different structure. It is an additional object to provide novel psoralen compounds having enhanced photosensitizing characteristics in accord with the foregoiny stated criteria. I~ is a s~ill rur~her object to provide novel psoralen compounds having enhanced photosensitiz-ing characteristics and relatively low toxicity, and of a structure differing essentially from known psoralen compounds, the advantageous properties of which could not be predicted on a basis of any known struc~ure-activity relationships. Still other objects will be apparent to one skilled in ~he art and still additi~nal objects will become apparent hereinafter from the following description and claims.

SUMMARY OF THE INVENTION
The present invention relates to 5'-aminoalkyl-4',4,8-trialkylpsoralens h~ving enhanced photosensitizing activity, especially oral activity, including early onset, increased maximum, and extended duration of activity, as well as low toxicity, when compared with psoralens of different structure.
Despite their different structure, the compounds are nev~heless charac~erized by excellent and superior photosensitization activity according to the aforesaid various critexia, as well as relatively low toxicity. The invention ic particularly con-cerned with 5'-primaryaminoloweralkyl-4',4,8-triloweralkyl-psoralens and especially 5'-aminomethyl-4,4',8-trimethylpsoralen.

The compounds of the invention have the formula I loweraLkyl aminoloweraIkyl ~ ~ ~ ~
lcweraIkyl ~

loweralkyl 5'-primaryaminoloweralkyl-4'-lowPralkyl-4-loweralkyl-8-lower-alkylpsoralen, wherein loweralkyl is preferably methyl.

DETAILED DESCRIPTION OF THE INVENTION
.
The following Preparations and Examples are given by way ,, ... ,.i , ~ ~5~2S ~

of illustration only and are not to be construed as limiting.
Appropriate starting umbelliferones ~4~alkyl and 4,8-di-alkyl-7-hydroxycoumarins) are known compounds which can be prepared in known manner and converted to a variety of alkyl-substituted psoralens by known procedure (MacLeod and Worth, Tetrahedron Lett., 237-240(1972)). Selected variations in the starting 4(and ~ alkyl substituents and in the alkylhalo-methyl ketone reactants produce the known 4,4',8-trimethyl-psoralen, and/or variations in the alkyl group at positions 4,4' and 8 of the resulting psoralen, as will appear more fully hereinafter, especially from the Examples which follow.
Chloroalkylation with a selected ~-chloroalkyl methyl ether introduces a desired and preselected chloroalkyl group into the 5' position of the 4',4,8-trialkylpsoralen nucleus, where-after reaction with potassium phthalimide followed by cleavage with hydrazine hydrate (hydrazinolysis) yields the desired 5'-aminoalkyl-4',4,8-trialkylpsoralen, in which the various alkyl groups correspond to those in the starting 4,8-dialkyl-7-hydroxycoumarin, the alkylhalomethyl ketone, and the chloro-alkylating agent employed. Alternatively, the haloalkylationmay be effected according to Olah and Kuhn, J. Org. Chem~ 29, 2317 (1964) or Friedel-Crafts and Related Reactions, Vol. II, Part 2, G~ A. Olah, ed., Interscience, New York, New York, 1964, page 749. The structure of the final 5'-aminoalkyl-4',4,8-tri-alkylps~ralen is confirmed by nuclear magnetic resonance spectra, using a Perkin Elmer ~Ddel P~-24B and elemental analysis. Melting points are uncorrected 5'-AMINOMETHYL-4',4,8-TRIMETHYLPSORALEN

.. . . . . . . _ 5~-Chloromethyl-4,4'~8-trimethylpsoralen. To a solution of 4,4l,8-TMP (29.36 g, 0,13 mol) in glacial acetic acid (1.3 L) was added chloromethyl methyl ether (200 mL) at room temperature~

1 15~2!~ ~
., After 48 hours a whiteprecipitate had formed and was filtered.
The crystals were air-dried to obtain 28.63 g (80%) of 5l-chloromethyl-4,4',8-trimethylpsoralen; mp 169-171C; NMP~
(CDC13) ~ 2.29 (s, 3H), 2.46 (s, 3H), 2.54 (s, 3H), 4.67 (s, 2H), 6.14 (s, lH), 7.3 (s, lH).
5'-N-Phthalimidometh~1-4,4',8-trimethylpsoralen.
solution of 5'-chloromethyl-4,4',8-trimethylpsoralen (13.63 g, 0.05 mol) and potassium phthalimide (11.1 g, 0.06 mol) in dimethylformamide (1.4 L~ was stirred at 100C for 6 hours. After cooling and diluting with water (3.0 L), the precipitate was collected and dried to obtain 17.95 g (92.7%) of 5'-N-~hthalimidomethyl-4,4',8-trimethylpsoralen.
5'-Aminomethyl-4,4',8-trimethylpsoralen~ A mixture of 5'-N-phthalimidomethyl-4,4',8-trimethylpsoralen (17~95 g, 0.046 mol), hydrazine hydrate (21.2 mL) and 95% ethanol ~2 L) was heaked under reflux for 6 hours and concentrate~ on a rotary evaporator to a residue which dissolved in 0.1_ NaOH (4.0 Ll.
Three portions (300 mL) of CHC13 extracted 5.8 g (49%) of a yellow solid, mp 193 - 201C. The solid was sublimed at 179C
for 36 hours to yield 2.5 g of material which, after recrystalliza-tion from benzene/ligroin, gave 1~9 gxams of moxe highly purified material; mp 197 - 199C; NMR (CDC13) ~ 1.7 (broad s, 2H), 2.21 (s, 3H), 2.44 (s, 3H), 2.48 (s, 3H), 3.93 (s, 2H), 6.15 (s,lH), 7.35 (s, lH). The product was subjected to elemental analysis and found to be 5'-aminomethyl-4,4',8-trimethylpsoralen~

. C . 15 15 3 ~ . ; , . 8; N, 5. 4.
Found: C, 69.74; H, 6.14; N, 5.68.
5'-AMINOETHYL-4'-ETHYL-4,8-DI~THYLPSORALEN. In the same manner as given in the foregoing, but using 4~-ethyl-4,8-dimethylpsoralen ~ 5 --IC EL~ER 9 ~ ~5~25 1 and a-chloroethyl methyl ether in Step 1, the title compound is produced.
5'-AMINOMETHYL-4',8-DIMETHYL~4-PROPYLPSORALEN. In the same _ manner as given in the foregoing, but using 4'~8-dimethyl-4-propylpsoralen in Step 1, the title compound is produced.
5'-AMINOMETHYL-4',4-DIMETHYL-8-ETHYLPSORALEN In the same _ manner as given in the foregoing, but starting from 4',4-dimethyl-8-ethylpsoralen in Step 1, the title compound is produced.
In the same manner as given in the foregoing, other variations in selection of starting materials are productive of still other 5'-aminoloweralkyl-4',4,8-triloweralkylpsoralens within the scope of the invention in which one, two, or all of the loweralkyl groups present in the compound are varied.
As used herein, the term "loweralkyl" comprehends such straight or branched radicals or gxoups having one to eight carbon atoms, preferably one to four carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, an~ the like.
The 5'-aminomethyl-4'-methylpsoralen was made in the same manner, star~ing from 7-hydroxycoumarin~ for comparison pur-poses. The final step of its preparation follows:

1 ~5825il PHA~MACOLOGY
The biophotosensitization activitv of the compounds of the present invention was determined by visual grading of ery- .
themal response according to a mo~ification of the procedure of Pathak and Fitzpatrick, J. Invest. Dermatol, 32, 509-518 (1959), entitled "Bioassay of Natural and Synthetic Furocoumarins (Psoralens)". (The psoralens are o~ course '~linear" isomers of the furocoumarin family.) According to this bioassay of photo-sensitizing potency, erythema product.ion on albino guinea pigsk~
is measured visually and the response accorded a gra~ation definition according to a 0, +, 1 r 2, 3~ and 4 scale. The ,nodification employed involved variation of the time between ad-ministration of the test compound and exposure to ultravioletlight, thereby enablin~ measurement of ~i~es of onset and decline of the induced photosensitivity e~fect.

P R O T O C O L S
Topical: Each drug i5 tested topically at a ~ncen ~ ~on of one percent (1%) in ethanolic ~olution. Test sites of ones~e centimeter of skin each receive one tenth rnilliliter of a~tiCU~
selected test solution thirty minutes prior to exposure to joules of ultraviolet "A" radiation. Three animals o fifteen in each group of guinea pigs are tested with each product to

2 ~ 1 ,, ~

arrive at an average response designated "Reaction Intensity"
which is determined by observation and grading 24 hours and 48 hours after administration.
Oral: Each drug is tested orally by administering a dosage of forty ~40) -mg/kgm of body weight to groups of fifteen guinea pigs. The appropriate dosage for each an~nal is packed into a gelatin capsule and placed far back in the aminal's pharynx. Swallowing is assisted by syringe delivery of three milliliters of water. The animals are not allowed to eat or drink six hours before and after administration of each product The exposure to ultraviolet "A" radiation is at a dose of two joules per square centimeter at different times after a~nistra-tion, e.g.~ 10, 20r 30~ 45r 60~ 90, 120~ 180, 240 and 360 minutes after administration. ReaLdings and evaluations are carried out 48 hours post ingestion. When a particular product is exceptionally active in the test, the per os dosage may of course be halved) halved again, or otherwise reduced.
Gradation: Responses are graded as follows:
0 No response; ~ faint erythema; l+ erythema; 2+ erythema 20 and slight edema; 3+ erythema and intense edema; and 4+
vesiculobullous reaction.

RESVLTS
The compounds of the invention show some erythematic toprcal activity as read at both 24 and 48 hours. They show oral activity as read at 48 hours which is outstanding, with high maxima, almost immediate onset, and long duration of photo~
sensitizing effect. The compound 5~-aminomethyl-4',4,8~tri-methylpsoralen is particularly outstanding, maintaining vesiculobullous response beyond 240 and through 360 minutes, with an early onset of intense erythema at only 10 minutes, main-~15~25~ TC ~LDER 9 .~

taining the maximum from 30 minutes through 360 minutes. It was only slightly less active at 20 mg/kg, and still of interest due to its quick, great and prolonged activity even at 10 mg/kg.
It is far superior in photosensitizing maximum, onset to maximum, and duration of maximum when compared wi-th 4'-amino-methyl-~,5',8-trimethylpsoralen. Its photosensitizing effi-ciency is still superior in all respects at the quartered oral dosage of 10 mg/kgm. In contrast, the 5'-aminomethyl-~'-methylpsoralen (made from 7 hydroxycoumarin) shows essentially no erythemic photosensitizing response orally, although it exhibits a 1~, 2+ topical response at 24 and 48 hours. The compounds of the invention show no oral toxicity, no animals dying at any of the dosage levels tested. In contrast, the compound 4' aminomethyl~4,5',8-trimethylpsoralen shows a high order of oral toxicity, a large number of the animals receiving 40 mg/kgm thereof dying during the period of their observation, the LD50 for that particular compound apparently being much less than this dosage level.
The biophotosensitization activity of the compounds of the invention is substantial in the erythemal response test according to the procedure of Patbak and Fitzpatrick, J. Invest.
Dermatol., 32, 509-518 (1959), entitled "~ioassay of Natural and Synthetic Furocoumarins ~Psoralens)", and usually employed standard modifications thereof, as reported hereinbefore. As "bio-photosensitization activity" is employed herein, however, as well as "photochemical sensitivity on the skin of a mammal", and "pnobochemotherapy~', the compounds of the invention are also active ~iophotosensitizing agents frcm another standpoint, inasmuch as they produce functional addition in the standrad tests for DN~ photoreactivity.

_ 9 _ 2 ~j ~

See, for example, Science 1977, 197 (4306), 906-908; J. Mol. siol.
1977, 116(4), ~61-679; Biochemistry 1977, 16 (6), 1058-1064, and related publications. The compounds are thus clearly useful in the further study of reactions and secondary structures of nucleic acids, and as inhibitors of RNA replication, and are indicated for employment in the inactivation of viruses as well as in the photochemotherapy of psoriasis by the PUVA procedure, in which they are found to be equally as effective as numerous previously-employed psoralen compounds. Their effectiveness is of course dependent upon numerous factors, such as amcunt of irradiation employed, dosage of the photosensitizing agent, mode of employment (whether topical or oral), and individual skin sensitivities of the mammal subjected to the P W A therapy, including of course human beings, with respect to which psoriasis is a unique malady. The compounds are accordingly useful for all of the foregoing purposes, but particularly for effecting photochemical sensitivity on the skin of a mammal, these terms as employed herein not being restricted to the production of erythema thereon, They are effective both orally and topically, and the method of effecting photochemical sensitivity on the skin of a mammal merely comprises the step of orally or topically administering to the said mammal an effective photosensitizing dose of a compound of the invention. When the subject is then exposed to ult-aviolet radiation, more particularly ultraviolet l'AI', in the non-burning range, f~nctional adducts with ~A
are formed and psoriasis is mitigated in human patients, as aforesaid. Other uses of the compounds of the present invention are also set forth in the foregoing.
The pharmaceutical compositions according to the present in-vention are suitable for use in effecting photochemical sensitivity on the skin of a mammal, particularly a human patient or subject, ~L5~2`51 !

and comprise an effective amount of a compound of the invention in association with a pharmaceutically-acceptable carrier or dil-uent. Such compositions are well-known in the art, and reference may again be made to U.SO Patents 4,124,598 and 4,130,568 for representative examples and disclosure concerning the same. The procedure for preparation of such compositions is totally con-ventional in the art. For oral treatment of psoriasis, the active ingredient is generally formulated in tablets or in gelatin cap-sules. ~n such case the diluent may, if desired, be eliminatedt although it is generally present. For topical application, solutions or ointments may be prepared and employed. These may be formulated with any one of a num~er of pharmaceutically-acceptable carriers, as is well known in the art. Administration may be, for example, in the form of tablets, capsules, powders, syrups, or solutions, or as already stated in the form of oint-ments, creams, or solutions ~or topical use. For tablet preparation, the usual tablet ~dju~ants such as cornstarch, potato starch~ talcum~ magnesium stearate, gelatin, lactose, gums, or the like may be employed, but any other pharmaceutical ~ tableting adjuvants may also be used, provided only -that they are compatible with the active ingredient. In general, an oral dosage regimen will include about 5 mg. to about 50 mg. per kg. of body weight, with a dose in the neighborhood of about 5-10 mg. per kg. generally being preferred. Such administration and selection of dosage and unit dosage will of ~ourse have to be determined according to established medical principles and under the supervision of the physician in charge of the PU~A
therapy involved. For topical use, only an effective amount of the active ingredient per unit area is involved, and this will illustratively be in the form of a one percent solution, suspen-TC E~.~ER 9 1 ~L5~25 ~

sion, or ointment thereof, illustratively applied on the orderof one-tenth mllliliter per square centimeter, in association with a sui~able carrier, e.g., ethanol, or other carrier of types already mentioned.
The amines of the present invention may conveniently be employed in the form of their pharmaceutically-acceptable acid addition saltsO When isolating compounds of the invention in the form of an acid addition salt, the acid is preferably selected so as to contain an anion which is non-toxic and pharmacologically acceptable, at least in usual therapeutic doses. Representative salts which are included in this pre-ferred group are the bicarbonates, hydrochlorides, hydrobromides, sulphates, acetates, phosphates, nitrates, methanesulphonates, ethanesulphonates, lactates, citrates, tartrates or bi~trates, and maleates. Other acids are likewise suita~le and may be employed if desired. For example, fumaric, benzoic, ascorbic, succinic, salicylic, bismethylenesalicylic, propionic, gluconic, malic, malonic, mandelic, cinnamic, citraconic, stearic, palmitic, itaconic, glycolic, benzenesulphonic, and sulphamic acids may also be employed as acid addition salt-forming acids.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Method of producing 5'-primaryaminoloweralkyl-4',4,8-triloweralkylpsoralen comprising the step of subjecting a 5'-imidoloweralkyl-4',4,8-triloweralkylpsoralen to hydra-zinolysis to produce the corresponding 5'-primaryaminolower-alkyl-4',4,8-triloweralkylpsoralen.

2. Method of Claim 1 wherein the product is 5'-aminomethyl-4',4,8-triloweralkylpsoralen and wherein the starting material is a 5'-imidomethyl-4',4,8-triloweralkylpsoralen.

3. Method of Claim 1 wherein the product is 5'-aminomethyl-4',4,8-trimethylpsoralen and wherein the starting material is 5'-phthalimidomethyl-4',4,8-trimethylpsoralen.

4. 5'-primaryaminoloweralkyl-4',4,8-triloweralkylpsoralen, whenever produced by the process of Claim 1 or an obvious chemical equivalent.

5. 5'-aminomethyl-4',4,8-triloweralkylpsoralen, whenever produced by the process of Claim 2 or an obvious chemical equivalent.

6. 5'-aminomethyl-4',4,8-trimethylpsoralen, whenever produced by the process of Claim 3 or an obvious chemical equivalent.

- 13 - (Claims page 1)

7. Method of Claim 1 wherein the product is 5'-aminomethyl-4',8-dimethyl-4-propylpsoralen and wherein the starting material is 4',8-dimethyl-4-propylpsoralen.

8. Method of Claim 1 wherein the product is 5'-aminomethyl-4',4-dimethyl-8-ethylpsoralen and wherein the starting material is 4',4-dimethyl-8-ethylpsoralen.

9. 5'-aminomethyl-4',8-dimethyl-4-propylpsoralen, whenever produced by the process of Claim 7 or an obvious chemical equivalent.

10. 5'-amminomethyl-4',4-dimethyl-8-ethylpsoralen, whenever produced by the process of Claim 8 or an obvious chemical equivalent.