Acid Addition Salts Of-5-Aminolevulinic Acid Or Its Derivatives

Abstract

The present invention provides an acid addition salt of 5-aminolevulinic acid (5-ALA) or of a 5-ALA derivative (e.g. a 5-ALA ester) with an acid which has a pKa of about 5 or less, preferably about 3 or less, with the proviso that the acid is other than hydrochloric acid. Particularly preferred salts are those derived from acids selected from the group comprising sulphonic acid and its derivatives, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. The salts in accordance with the invention are particularly suitable for use as photosensitizing agents in diagnosis and photochemotherapy of disorders or abnormalities of external or internal surfaces of the body.

Description

The invention will now be described in more detail in the following non-limiting Examples, with reference to the drawings in which:

FIG. 1 shows skin fluorescence following topical application of cream formulations containing different salts of 5-amino-4-oxopentanoic acid, bars indicate standard deviation;

FIG. 2 shows skin fluorescence following topical application of cream formulations containing hydrochloride, tosylate and mesylate salts of benzyl 5-amino-4-oxopentanoate, bars indicate standard deviation;

FIG. 3 shows skin fluorescence following topical application of cream formulations containing hydrochloride and methanesulfonate salts of methyl 5-amino-4-oxopentanoate, bars indicate standard deviation;

FIG. 4 shows skin fluorescence following topical application of cream formulations containing hydrochloride, methanesulfonate and toluenesulfonate salts of methyl 5-amino-4-oxopentanoate, bars indicate standard deviation;

FIG. 5 shows skin fluorescence following topical application of cream formulations containing hydrochloride and hydrobromide salts of 5-amino-4-oxopentanoic acid, bars indicate standard deviation;

FIG. 6 shows skin fluorescence following topical application of cream formulations containing hydrochloride, hydrobromide and nitrate salts of benzyl 5-amino-4-oxopentanoic acid, bars indicate standard deviation;

FIG. 7 shows skin fluorescence following topical application of cream formulations containing hydrochloride, sulphate and phosphate salts of benzyl 5-amino-4-oxopentanoic acid, bars indicate standard deviation;

FIG. 8 shows the hygroscopicity of hydrochloride, methanesulfonate and toluenesulfonate salts of methyl 5-amino-4-oxopentanoic acid;

FIG. 9 shows the hygroscopicity of hydrochloride and toluenesulfonate salts of 5-amino-4-oxopentanoic acid; and

FIG. 10 shows the hygroscopicity of hydrochloride, methanesulfonate and toluenesulfonate salts of hexyl 5-amino-4-oxopentanoic acid.

EXAMPLE 1

Preparation of Hexyl 5-amino-4-oxopentanoate Toluenesulfonate

Sodium hydrogen carbonate (0.42 g; 5.0 mmol) was added to a solution of hexyl 5-amino-4-oxopentanoate hydrochloride (0.5 g; 2.0 mmol) in water (10 ml) and dichloromethane (5 ml). The mixture was shaken thoroughly and allowed to separate. The organic layer was pipetted off and added to p-toluenesulfonic acid (0.38 g; 2.0 mmol). The aqueous portion was extracted with dichloromethane (1×1 ml). The combined organic solutions were evaporated, leaving a yellow oil that solidified on overnight storage in a freezer. The residue was purified by flash chromatography on a 170×25 mm silica gel 60 column eluted with acetonitrile (150 ml), 5% methanol in acetonitrile (500 ml), and 10% methanol in acetonitrile (250 ml), collecting 15×50 ml fractions. Fractions containing the product were evaporated, leaving 0.31 g (40%) residue.

¹H NMR: (200 MHz; DMSO-d₆): δ 0.87 (3H, t, J=7 Hz) 1.26 (6H, br s), 1.56 (2H, m), 2.29 (3H, s), 2.54 (2H, t, J=7 Hz), 2.79 (2H, t, J=6 Hz), 4.0 (4H, m), 7.12 (2H, d, J=8 Hz), 7.48 (2H, d, J=8 Hz), 8.04 (3H, br s).

EXAMPLE 2

Preparation of Hexyl 5-amino-4-oxopentanoate Methanesulfonate (Ion-exchange Method)

A solution of hexyl 5-amino-4-oxopentanoate hydrochloride (1.0 g; 4.0 mmol) in water (5 ml) and 96% ethanol (5 ml) was passed through a column of Amberlyst A-26(OH) (2.1 g; 8.8 meq) into a solution of methanesulfonic acid (0.38 g; 4.0 mmol) in water (3 ml). The resin column was washed with 50% aq. ethanol (10 ml) and the combined eluents were evaporated to dryness. After drying overnight, the residue was purified by flash chromatography on a 170×25 mm silica gel 60 column eluted with acetonitrile (200 ml), 5% methanol in acetonitrile (500 ml), 7.5% methanol in acetonitrile (500 ml) and 10% methanol in acetonitrile (750 ml), collecting 27×50 ml fractions. Evaporation of fractions containing product gave 0.77 g (62%) residue, mp 132-134° C.

¹H NMR: (200 MHz; DMSO-d₆) δ 0.87 (3H, t, J=6 Hz), 1.27 (6H, br s), 1.56 (2H, m, J=6 Hz), 2.35 (3H, s), 2.55 (2H, t, J=6 Hz), 2.80 (2H, t, J=6 Hz), 4.00 (4H, m), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 13.8, 21.8, 24.9, 27.0, 30.8, 34.1, 39.5, 46.6, 64.0, 171.8, 202.4.

EXAMPLE 3

Benzyl 5-amino-4-oxopentanoate Methanesulfonate.

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and methanesulfonic acid using the ion-exchange method, mp 110-115° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.36 (3H, s), 2.63 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 3.99 (2H, s), 5.10 (2H, s), 7.37 (5H, m), 8.10 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): 6 27.0, 34.1, 39.5, 46.6, 65.5, 127.6, 127.8, 128.2, 135.9, 171.7, 202.4.

EXAMPLE 4

Benzyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and p-toluenesulfonic acid using the ion-exchange method, mp 120-125° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.29 (3H, s), 2.62 (2H, t, J=6 Hz), 2.83 (2H, t, J=6 Hz), 3.99 (2H, s), 5.10 (2H, s), 7.12 (2H, d, J=8 Hz), 7.37 (5H, s), 7.50 (2H, d, J=8 Hz), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆) δ 20.7, 27.0, 34.1, 46.6, 65.5, 127.6, 127.8, 127.9, 128.2, 135.9, 137.6, 145.2, 171.7, 202.4.

EXAMPLE 5

Preparation of 5-amino-4-oxopentanoic Acid Methanesulfonate (Silver Salt Method)

A solution of 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) in water (5 ml) was added to a stirred solution of silver methanesulfonate (1.22 g; 6.0 mmol) in water (10 ml) in a stoppered erlenmeyer flask wrapped with aluminum foil. The mixture was stirred overnight and transfered to centrifuge tubes. The mixture was centrifuged and decanted. The residue was washed with water (2×1 ml). After centrifuging, the combined aqueous solutions were freeze-dried overnight to give 5-amino-4-oxopentanoic acid methanesulfonate (1.3 g; 96% yield), mp 153.5-154.5° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.39 (3H, s), 2.50 (2H, t, J=6 Hz), 2.72 (2H, t, J=4 Hz), 3.97 (2H, s), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 27.2, 34.2, 39.5, 46.6, 173.2, 202.6

EXAMPLE 6

5-Amino-4-oxopentanoic Acid Toluenesulfonate

Prepared from 5-amino-4-oxopentanoic acid hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 185-186° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.29 (3H, s), 2.49 (2H, t, J=6 Hz), 2.74 (2H, t, J=6 Hz), 3.97 (2H, s), 7.12 (2H, d, J=7 Hz), 7.48 (2H, d, J=8 Hz), 8.03 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 20.7, 27.1, 34.2, 46.6, 125.2, 127.8, 138, 145, 173.1, 202.6.

EXAMPLE 7

Methyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from methyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 135-137° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.29 (3H, s), 2.54 (2H, t, J=8 Hz), 2.79 (2H, t, J=6 Hz), 3.59 3H, s), 3.98 (2H, s), 7.13 (2H, d, J=8 Hz), 7.50 (2H, d, J=8 Hz), 8.07 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 20.7, 26.8, 34.1, 46.6, 51.4, 125.3, 127.9, 137.7, 145.1, 172.2, 202.4.

EXAMPLE 8

Methyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from methyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 138-140° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.29 (3H, s), 2.54 (2H, t, J=8 Hz), 2.79 (2H, t, J=6 Hz), 3.59 3H, s), 3.98 (2H, s), 7.13 (2H, d, J=8 Hz), 7.50 (2H, d, J=8 Hz), 8.07 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆) δ 20.7, 26.8, 34.1, 46.6, 51.4, 125.3, 127.9, 137.7, 145.1, 172.2, 202.4.

EXAMPLE 9

Hexyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from hexyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 125° C. and 134-136° C. (different crystalline forms).

¹H NMR: (200 MHz; DMSO-d₆) δ 0.87 (3H, t, J=6 Hz), 1.27 (6H, br s), 1.56 (2H, m, J=6 Hz), 2.35 (3H, s), 2.55 (2H, t, J=6 Hz), 2.80 (2H, t, J=6 Hz), 4.00 (4H, m), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 13.8, 21.8, 24.9, 27.0, 30.8, 34.1, 39.5, 46.6, 64.0, 171.8, 202.4.

EXAMPLE 10

Hexyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from hexyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 116-118° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 0.86 (3H, t, J=6 Hz) 1.26 (6H, br s), 1.53 (2H, m), 2.29 (3H, s), 2.53 (2H, t, J=6 Hz), 2.78 (2H, t, J=6 Hz), 4.0 (4H, m), 7.12 (2H, d, J=8 Hz), 7.50 (2H, d, J=8 Hz), 8.06 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 13.8, 20.7, 21.9, 24.9, 27.0, 28.0, 30.8, 34.1, 46.6, 64.0, 125.3, 127.9, 137.6, 145.2, 171.8, 202.4.

EXAMPLE 11

2-Methyl-1-pentyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from 2-methyl-1-pentyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 128-133° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 0.88 (6H, m), 1.0-1.4 (4H, m), 1.74 (1H, m, J=6 Hz), 2.35 (3H, s), 2.56 (2H, t, J=6 Hz), 2.81 (2H, t, J=8 Hz), 3.75-3.96 (2H, m), 3.97 (2H, s), 8.12 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 14.0, 16.5, 19.3, 23.6, 27.0, 31.6, 34.1, 34.9, 39.5, 46.6, 68.6, 171.8, 202.4.

EXAMPLE 12

2-Methyl-1-pentyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from 2-methyl-1-pentyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 125-127° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 0.88 (6H, t, J=6 Hz), 1.0-1.4 (4H, m), 1.73 (1H, m), 2.29 (3H, s), 2.56 (2H, t, J=6 Hz), 2.80 (2H, t, J=6 Hz), 3.75-4.0 (2H, m), 3.98 (2H, s), 7.12 (2H, d, J=8 Hz), 7.49 (2H, d, J=8 Hz), 8.03 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 14.0, 16.5, 19.3, 20.7, 23.6, 26.9, 31.6, 34.1, 34.8, 46.6, 68.6, 125.3, 127.8, 137.4, 145.2, 171.8, 202.4.

EXAMPLE 13

4-Methyl-1-pentyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from 4-methyl-1-pentyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 75-85° C. and 110-115° C. (different crystalline forms).

¹H NMR: (200 MHz; DMSO-d₆): δ 0.86 (6H, d, J=6 Hz) 1.20 (2H, m), 1.53 (2H, m, 2.39 (3H, s), 2.55 (2H, t, J=6 Hz), 2.80 (2H, t, J=8 Hz), 3.90-4.04 (4H, m), 8.18 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 22.3, 25.9, 27.0, 27.0, 34.1, 34.3, 39.5, 46.6, 64.2, 171.8, 202.4.

EXAMPLE 14

4-Methyl-1-pentyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from 4-methyl-1-pentyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 96-100° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 0.86 (6H, t, J=6 Hz), 1.16 (2H, m), 1.53 (1H, m), 2.29 (3H, s), 2.57 (2H, t, J=6 Hz), 2.78 (2H, t, J=6 Hz), 3.95-4.05 (4H, m), 7.13 (2H, d, J=8 Hz), 7.51 (2H, d, J=8 Hz), 8.06 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 20.7, 22.3, 25.9, 27.0, 27.0, 34.1, 34.3, 46.6, 64.2, 125.3, 127.9, 137.6, 145.1, 171.8, 202.4.

EXAMPLE 15

2-(2-Ethoxyethoxy)ethyl 5-amino-4-oxopentanoate Benzenesulfonate

Prepared from 2-(2-ethoxyethoxy)ethyl 5-amino-4-oxopentanoate hydrochloride and silver benzenesulfonate using the silver salt method, mp 52-56° C.

¹H NMR: (200 MHz; DMSO-d₆) δ 1.10 (3H, t, J=7 Hz) 2.57 (2H, t, J=6 Hz), 2.79 (2H, t, J=6 Hz), 3.35-3.65 (8H, m), 3.98 (2H, s), 4.12 (2H, t, J=5 Hz), 7.25-7.36 (3H, m), 7.55-7.65 (2H, m), 8.04 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 15.0, 27.0, 34.1, 46.6, 63.4, 65.5, 68.0, 69.0, 69.7, 125.3, 127.4, 128.3, 147.8, 171.8, 202.4.

EXAMPLE 16

Benzyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 132-135° C.

¹H NMR: (200 MHz; DMSO-d₆) δ 2.36 (3H, s), 2.63 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 3.99 (2H, s), 5.10 (2H, s), 7.37 (5H, m), 8.10 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 27.0, 34.1, 39.5, 46.6, 65.5, 127.6, 127.8, 128.2, 135.9, 171.7, 202.4.

EXAMPLE 17

Benzyl 5-amino-4-oxopentanoate 2-hydroxyethanesulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver 2-hydroxyethanesulfonate using the silver salt method, mp 76-82° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.63 (2H, t, J=6 Hz), 2.67 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 3.65 (2H, t, J=7 Hz), 3.98 (2H, s), 5.10 (2H, s), 7.37 (5H, m), 8.13 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆) δ 27.0, 34.1, 46.6, 53.5, 57.5, 65.5, 127.6, 127.8, 128.2, 135.9, 171.7, 202.4.

EXAMPLE 18

Benzyl 5-amino-4-oxopentanoate (1S)-10-camphorsulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver (1S)-10-camphorsulfonate using the silver salt method, viscous oil.

¹H NMR: (200 MHz; DMSO-d₆): δ 0.75 (3H, s), 1.04 (3H, s) 1.31 (2H, m), 1.75-1.97 (3H, m), 2.24 (1H, dt, J=4 and 18 Hz), 2.40 (1H, d, J=16 Hz), 2.63 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 2.90 (1H, d, J=16 Hz), 3.99 (2H, s), 5.10 (2H, s), 7.36 (5H, s), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 19.4, 20.0, 24.0, 26.3, 27.0, 42.0, 42.1, 42.1, 46.5, 46.6, 46.9, 58.1, 65.5, 127.6, 127.8, 128.2, 135.9, 171.7, 202.4, 216.0.

EXAMPLE 19

Benzyl 5-amino-4-oxopentanoate Benzenesulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver benzenesulfonate using the silver salt method, mp 100-103° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.62 (2H, t, J=6 Hz), 2.83 (2H, t, J=6 Hz), 3.99 (2H, s), 5.10 (2H, s), 7.30-7.40, 7.60-7.70 (10H, m), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 27.0, 34.1, 46.6, 65.5, 122.9, 125.3, 127.5, 127.6, 127.8, 128.2, 128.2, 135.9, 147.8, 171.7, 202.4.

EXAMPLE 20

Benzyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 146-148° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.29 (3H, s), 2.62 (2H, t, J=6 Hz), 2.83 (2H, t, J=6 Hz), 3.99 (2H, s), 5.10 (2H, s), 7.12 (2H, d, J=8 Hz), 7.37 (5H, s), 7.50 (2H, d, J=8 Hz), 8.08 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 20.7, 27.0, 34.1, 46.6, 65.5, 127.6, 127.8, 127.9, 128.2, 135.9, 137.6, 145.2, 171.7, 202.4.

EXAMPLE 21

Benzyl 5-amino-4-oxopentanoate 2-naphthalenesulfonate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver 2-naphthalenesulfonate using the silver salt method, mp 137-141° C. (dec.).

¹H NMR: (200 MHz; DMSO-d₆): δ 2.62 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 4.00 (2H, s), 5.10 (2H, s), 7.12 (2H, d, J=8 Hz), 7.36 (5H, s), 7.49 (2H, m), 7.74 (1H, dd, J=2 and 8 Hz), 7.86-8.00 (4H, m), 8.18 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 27.0, 34.1, 46.6, 65.5, 123.7, 123.9, 126.1, 126.3, 127.2, 127.6, 127.8, 128.2, 131.9, 132.6, 134.7, 135.9, 137.6, 145.1, 171.7, 202.4.

EXAMPLE 22

4-Methylbenzyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from 4-methylbenzyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 120-124° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.30 (3H, s), 2.36 (3H, s) 2.61 (2H, t, J=6 Hz), 2.83 (3H, m), 3.98 (2H, s), 5.05 (2H, s), 7.22 (4H, m), 8.14 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 20.6, 23.6, 27.0, 34.1, 39.5, 46.6, 65.4, 127.8, 128.8, 132.8, 137.1, 171.7, 202.4.

EXAMPLE 23

4-Methylbenzyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from 4-methylbenzyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 115-119° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.29 (3H, s), 2.30 (3H, s) 2.59 (2H, t, J=6 Hz), 2.82 (3H, m), 3.97 (2H, s), 5.04 (2H, s), 7.19 (6H, m, J=8 Hz), 7.50 (2H, d, J=8 Hz), 8.18 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆) 20.7, 27.0, 34.1, 46.5, 65.4, 125.3, 127.8, 127.9, 128.8, 132.8, 137.1, 137.6, 145.2, 171.7, 202.4

EXAMPLE 24

4-Isopropylbenzyl 5-amino-4-oxopentanoate Methanesulfonate

Prepared from 4-isopropylbenzyl 5-amino-4-oxopentanoate hydrochloride and silver methanesulfonate using the silver salt method, mp 113-115° C. and 125-127° C. (different crystalline forms).

¹H NMR: (200 MHz; DMSO-d₆): δ 1.20 (6H, d, J=6 Hz) 2.36 (3H, s), 2.62 (2H, t, J=6 Hz), 2.85 (3H, m), 3.99 (2H, s), 5.06 (2H, s), 7.27 (4H, m), 8.15 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 23.7, 27.0, 33.1, 34.1, 39.5, 46.6, 65.4, 126.1, 127.9, 133.2, 148.1, 171.7, 202.4.

EXAMPLE 25

4-Isopropylbenzyl 5-amino-4-oxopentanoate Toluenesulfonate

Prepared from 4-isopropylbenzyl 5-amino-4-oxopentanoate hydrochloride and silver p-toluenesulfonate using the silver salt method, mp 121-123° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 1.20 (6H, d, J=6 Hz), 2.29 (3H, s), 2.60 (2H, t, J=6 Hz), 2.82 (2H, t, J=6 Hz), 2.88 (1H, m), 3.98 (2H, s), 5.05 (2H, s), 7.12 (2H, d, J=8 Hz), 7.26 (4H, d, J=2 Hz), 7.50 (2H, d, J=8 Hz), 8.10 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆) δ 20.7, 2.7, 27.0, 33.1, 34.1, 46.6, 65.4, 125.3, 126.1, 127.8, 133.2, 137.5, 145.5, 148.1, 171.7, 202.4.

EXAMPLE 26

5-amino-4-oxopentanoic Acid Hydrobromide

A stirred mixture of methyl 5-phthalimido-4-oxopentanoate (4.0 g, 14.5 mmol) [Z. Naturforsch. 41B, 1593-94 (1986)] and 48% hydrobromic acid (40 ml) was refluxed for 7 hrs, then cooled to room temperature and stored overnight in a refrigerator. Following filtering the residue was washed with water and the combined filtrates were evaporated to dryness on a rotary evaporator and titrated with diethyl ether (2×25 ml). The residue was filtered and dried over silica gel at 30° C. and 15 mm Hg in a drying pistol. The crude product was dissolved in methanol (10 ml) and 2-propanol (30 ml). Diethyl ether (150 ml) was added and the mixture was allowed to stand 2 hrs. The precipitate was filtered and dried as before, to give 2.5 g (81%), mp 137-140° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.49 (2H, t, J=6 Hz), 2.76 (2H, t, J=6 Hz), 3.99 (2H, s), 8.13 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆) δ 27.1, 34.3, 46.6, 173.1, 202.5.

EXAMPLE 27

Benzyl 5-amino-4-oxopentanoate Hydrobromide

A stirred mixture of 5-amino-4-oxopentanoic acid hydrobromide (1.60 g, 7.5 mmol), benzyl alcohol (15 ml), and 48% hydrobromic acid (8 drops) was heated to 80° C. (bath temperature) for 2 days. The mixture was cooled to room temperature and excess benzyl alcohol was removed with a rotary evaporator at 0.12 mm Hg. The residue was titrated with diethyl ether (2×50 ml) and the residue was purified by flash chromatography on a 160×55 mm silica gel 60 column eluted sequentially with acetonitrile, 50 methanol in acetonitrile, and 10% methanol in acetonitrile. Fractions containing the product were combined and evaporated. The residue was titruated with diethyl ether (5×15 ml), filtered, and dried at 30° C. and 15 mm Hg to give 0.97 g (43%) tan powder, mp 62-67° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.63 (2H, t, J=6 Hz), 2.86 (2H, t, J=6 Hz), 4.02 (2H, s), 5.10 (2H, s), 7.37 (5H, s), 8.16 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ27.0, 34.2, 39.5, 46.5, 65.5, 127.6, 127.8, 128.2, 135.9, 171.7, 202.3.

EXAMPLE 28

Benzyl 5-amino-4-oxopentanoate Nitrate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and silver nitrate using the silver salt method, mp 82-86° C.

¹H NMR: (200 MHz; DMSO-d₆): δ 2.63 (2H, t, J=6 Hz) 2.84 (2H, t, J=6 Hz), 4.00 (2H, s), 5.10 (2H, s), 7.37 (5H, s), 8.10 (3H, br s).

¹³C NMR: (50 MHz; DMSO-d₆): δ 27.0, 34.1, 39.5, 46.6, 65.5, 127.6, 127.8, 128.2, 135.9, 171.7, 202.4.

EXAMPLE 29

Benzyl 5-amino-4-oxopentanoate Sulfate (2:1)

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride (0.52 g; 2.0 mmol) and Ag₂SO₄ (0.31 g; 1.0 mmol) in water (10 mL) using the silver salt method. Yield after drying over silica gel was 0.51 g (94%). Mp 106-109° C.

Elemental analysis (carried out by Ilse Beetz Mikroanalytisches Laboratorium, 96301 Kronach, Germany):

	% C	calc. 53.32%	found 53.37%
	% H	calc.  5.97%	found  5.97%
	% S	calc.  5.93%	found  5.78%

The elemental analysis shows that the product exists as the sulfate (2:1), i.e. (benzyl 5-amino-4-oxopentanoate)₂SO₄

EXAMPLE 30

Benzyl 5-amino-4-oxopentanoate Phosphate

Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride (0.52 g; 2.0 mmol) and Ag₃PO₄ (0.28 g; 0.67 mmol) in water (10 mL) using the silver salt method. Yield after drying over silica gel was 0.36 g. Mp 93-95° C.

Elemental analysis (carried out by Ilse Beetz Mikroanalytisches Laboratorium, 96301 Kronach, Germany):

	PO43−	HPO42−
	% C	calc. 56.76%	calc. 53.33%	found 53.62%
	% H	calc. 6.35%	calc. 6.15%	found 6.08%
	% P	calc. 4.07%	calc. 5.73%	found 3.90%

The elemental analysis indicates that the product is not the expected phosphate (3:1); the closest match for C and H is the monohydrogen phosphate (benzyl 5-amino-4-oxopentanoate)₂HPO₄. The comparatively low value for P could be caused by incomplete reaction, e.g. some chloride may still be present.

EXAMPLE 31

Formulations

Different salts of 5-amino-4-oxopentanoic acid or of its esters were formulated in Unguentum Merck for dermal studies. All cream formulations contained 0.5 mmol of substance per 10 g cream to ensure the same molar concentration (assuming that 10 g cream equals 10 ml, the approx. molar concentration is 0.5 mmol/10 ml or 50 mM). Preparation of the formulations is outlined in Table 1 below.

TABLE 1
Dermal formulations
	Mol.	Formulation**
Substance-salt*	wt.	(mg/10 g cream)
5-amino-4-oxopentanoic acid-HCl	168	85
5-amino-4-oxopentanoic	211	105
acid-methanesulfonate
hexyl 5-amino-4-oxopentanoate-HCl	251	125
hexyl	294	150
5-amino-4 oxopentanoate-methanesulfonate
hexyl	372	190
5-amino-4-oxopentanoate-toluenesulfonate
methyl 5-amino-4-oxopentanoate-HCl	181	100
methyl	224	125
5-amino-4-oxopentanoate-methanesulfonate
methyl 5-amino-4-oxopentanoate-	302	170
toluenesulfonate
benzyl 5-amino-4-oxopentanoate-HCl	258	130
benzyl	301	150
5-amino-4-oxopentanoate-methanesulfonate
benzyl	379	190
5-amino-4-oxopentanoate-toluenesulfonate
(a)
*All salts were prepared by the silver salt method except for the substance marked with (a) which was prepared by the ion exchange method.
**All formulations contained 0.5 mmol salt per 10 g cream

EXAMPLE 32

Biological Activity—Salts of 5-amino-4-oxopentanoic Acid

Method: Female Balb/c athymic nude mice, weighing about 22 g, obtained from the Department of Laboratory Animals, The Norwegian Radium Hospital, Oslo, Norway, were used in the study. Each group consisted of three mice.

Each mouse received 0.05-0.1 g of formulation (see Example 31) topically applied at the right flank of the body, evenly distributed and covered with a dressing (Opsite Flexigrid; Smith and Nephew Medical Ltd., Hull, England).

The fiber point measuring device used consisted of a bundle of optical fibers connected to a spectrofluorimeter which produced the excitation light of 407 nm. The excitation light, which is capable of penetrating 0.1-0.5 mm into the tissue, was led through half of the fibers to the mouse skin. The resulting emission fluorescence spectrum (550-750) nm was collected and led through the remaining fibers into a photomultiplier for quantification. The fluorescence spectrum from the skin was measured at 0, 2, 4, 6, 8, 10, 12 and 24 hours after administration and plotted against time.

Results: It can be seen from FIG. 1 that the methanesulfonate salt gave somewhat higher maximal skin fluorescence than the HCl salt.

EXAMPLE 33

Biological Activity—Salts of Benzyl 5-amino-4-oxopentanoate

Preparation of formulations is described in Example 31. The same experimental system as in Example 32 was used, and the results are shown in FIG. 2.

It can be seen from FIG. 2 that both the methanesulfonate and the toluenesulfonate salts gave 25-30% higher maximal fluorescence than the hydrochloride salt. Both the initial fluorescence build-up occurred faster and the maximum fluorescence occurred faster for the methanesulfonate and the toluenesulfonate salts than for the hydrochloride salt.

EXAMPLE 34

Biological Activity—Salts of Methyl 5-amino-4-oxopentanoate

Preparation of formulations is described in Example 31. The same experimental system as in Example 32 was used, and the results are shown in FIG. 3.

It can be seen from FIG. 3 that the methanesulfonate-salt of methyl 5-aminolevulinate gave a considerable increase in skin fluorescence as compared to the hydrochloride salt.

EXAMPLE 35

Biological Activity—Salts of Hexyl 5-amino-4-oxopentanoate

Preparation of formulations is described in Example 31. The same experimental system as in Example 32 was used, and the results are shown in FIG. 4.

It can be seen from FIG. 4 that the methanesulfonate- and toluenesulfonate salts of hexyl 5-aminolevulinate gave approx. the same skin fluorescence as the hydrochloride salt.

EXAMPLE 36

Formulations

Different salts of 5-amino-4-oxopentanoic acid or of its benzylester were formulated in Unguentum Merck for dermal studies. All cream formulations contained 0.5 mmol substance per 10 g cream to assure the same molar concentration. Corrections were made in the case of the 2:1 salts so that the molar concentration of 5-amino-4-oxopentanoic acid or the corresponding ester corresponded to 0.5 mmol/10 g cream. Assuming that 10 g cream equals 10 ml, the approx. molar concentration is 0.5 mmol/10 ml=50 mM. Preparation of the formulations is outlined in Table 2 below.

TABLE 2
Dermal formulations
		Formulation
Substance-salt	Mol. wt	(mg/10 g cream)
5-amino-4-oxopentanoic acid-HCl	168	85
5-amino-4-oxopentanoic acid-HBr	213	107
benzyl 5-amino-4-oxopentanoate-HCl	258	130
benzyl 5-amino-4-oxopentanoate-HBr	302	151
benzyl 5-amino-4-oxopentanoate-HNO3	284	142
benzyl 5-amino-4-oxopentanoate-	378	189
benzenesulphonate
benzyl 5-amino-4-oxopentanoate-	269*	135
sulphate
benzyl 5-amino-4-oxopentanoate-	261*	131
phosphate
*Assuming ½ mole of sulphate or hydrogenphosphate per mole of benzyl 5-amino-4-oxopentanoate.

EXAMPLE 37

Biological Activity—Salts of 5-amino-4-oxopentanoic Acid

Preparation of the formulations is described in Example 36. The same experimental system as in Example 32 was used, except that the skin fluorescence was measured at 636 nm rather than at 550-750 nm. The results are shown in FIG. 5.

EXAMPLE 38

Biological Activity—Salts of Benzyl 5-amino-4-oxopentanoate

Preparation of the formulations is described in Example 36. The same experimental system as in Example 37 was used. The results are shown in FIGS. 6 and 7.

It can be seen from FIG. 6 that the nitrate salt of benzyl 5-amino-4-oxopentanoate was more effective in inducing skin fluorescence than the hydrochloride salt.

It can be seen from FIG. 7 that the sulphate- and phosphate-salts of benzyl 5-amino-4-oxopentanoate were poorer inducers of skin fluorescence than the corresponding hydrochloride salt. However, the maximum fluorescence occurred earlier for the sulphate- and phosphate-salts than for the hydrochloride salt.

EXAMPLE 39

Hygroscopicity of Hexyl 5-amino-4-oxopentanoate Hydrochloride, Methanesulfonate, and Toluenesulfonate

Samples (2 mg) of the hydrochloride, methanesulfonate, and toluenesulfonate of hexyl 5-amino-4-oxopentanoate were kept at ambient temperature and ambient humidity for 4 days. No observable change.

Samples (2 mg) of the hydrochloride, methanesulfonate, and toluenesulfonate of hexyl 5-amino-4-oxopentanoate were kept at ambient temperature and 100% humidity. The hydrochloride had deliquesced after standing overnight. The methanesulfonate had deliquesced after two days, while the toluenesulfonate had deliquesced after four days.

EXAMPLE 40

Hygroscopicity of Methyl 5-amino-4-oxopentanoate Hydrochloride, Methanesulfonate, and Toluenesulfonate

Samples of methyl 5-amino-4-oxopentanoate hydrochloride, methanesulfonate, and toluenesulfonate were weighed and kept in 30 ml plastic cups in a closed chamber at 75-84% relative humidity over saturated ammonium sulfate solution at ambient temperature (ca. 25° C). The samples were then weighed after different intervals of time to monitor water uptake. The appearance of the samples was also checked at the same time to determine the onset of deliquescence. The results are shown in FIG. 8.

It can be seen from FIG. 8 that both the hydrochloride and mesylate salts took up water to a considerable extent as monitored by weight and that the onset of deliquescence occurred after 22 hrs (as indicated by asterisks in the figure). In contrast, the tosylate salt of methyl 5-amino-4-oxopentanoate did not pick up water and did not change appearance during the test period.

EXAMPLE 41

Hygroscopicity of 5-amino-4-oxopentanoic Acid Hydrochloride, Methanesulfonate, and Toluenesulfonate

Samples of 5-amino-4-oxopentanoic acid hydrochloride and toluenesulfonate were weighed and kept in 30 ml plastic cups in a closed chamber at 75-84% humidity over saturated ammonium sulfate solution at ambient temperature (ca. 25° C.). The samples were then weighed after different intervals of time to monitor water uptake. The appearance of the samples was also checked at the same time to determine the onset of deliquescence. The results are shown in FIG. 9.

It can be seen from FIG. 9 that the hydrochloride salt of 5-amino-4-oxopentanoaic acid took up water to a considerable extent as monitored by weight. The onset of deliquescence for the hydrochloride salt occurred after 22.5 hrs (as indicated by an asterisk in the figure). In contrast the tosylate salt did not pick up water and did not change appearance during the test period.

EXAMPLE 42

Hygroscopicity of Hexyl 5-amino-4-oxopentanoate Hydrochloride, Methanesulfonate, and Toluenesulfonate

Samples of hexyl 5-amino-4-oxopentanoate hydrochloride and toluenesulfonate were weighed and kept in 30 ml plastic cups in a closed chamber at 75-84% relative humidity over saturated ammonium sulfate solution at ambient temperature (ca. 25° C.). The samples were then weighed after different intervals of time to monitor water uptake. The appearance of the samples was also checked at the same time to determine the onset of deliquescence. The results are shown in FIG. 10.

It can be seen in FIG. 10 that the hydrochloride salt of hexyl 5-amino-4-oxopentanoate did not pick up water to a considerable extent as monitored by weight, but the onset of deliquescence occurred after only 5.0 hrs (as indicated by an asterisk in the figure). The mesylate salt took up water to some extent, but deliquescence did not occur. The tosylate salt of hexyl 5-amino-4-oxolevulinate did not pick up water and did not change appearance during the test period.

Claims

1. An acid addition salt of a 5-aminolevulinic acid (5-ALA) derivative with an acid which has a pKa of about 5 or less, wherein said acid is a sulfonic acid, a sulfonic acid derivative, sulfuric acid, nitric acid or phosphoric acid.

2. An acid addition salt as claimed in claim 1 which is derived from a compound of formula X: R22N—CH2COCH2—CH2CO—OR1  (X)

3. An acid addition salt as claimed in claim 2, wherein in formula X, R1 either represents an unsubstituted alkyl group or an alkyl group substituted by an aryl group and/or each R2 represents a hydrogen atom.

4. An acid addition salt as claimed in claim 2 or claim 3, wherein R1 is a benzyl or substituted benzyl group.

5. An acid addition salt as claimed in claim 2, wherein said compound of formula X is 5-ALA methyl ester, 5-ALA hexyl ester, 5-ALA benzyl ester, 5-ALA 2-methylpentyl ester, 5-ALA 4-methylpentyl ester, 5-ALA 2-(2-ethoxyethoxy)ethyl ester, 5-ALA 4-methylbenzyl ester or 5-ALA 4-isopropylbenzyl ester.

6. An acid addition salt as claimed in claim 2, wherein said compound of formula X is 5-ALA methyl ester, 5-ALA hexyl ester or 5-ALA benzyl ester.

7. An acid addition salt as claimed in claim 1, wherein said acid is an organic acid.

8. An acid addition salt as claimed in claim 7, wherein said acid is a sulfonic acid or a sulfonic acid derivative.

9. An acid addition salt as claimed in claim 1 of formula I:

10. An acid addition salt as claimed in claim 9, wherein R is optionally substituted phenyl or methyl.

11. An acid addition salt as claimed in claim 9 or claim 10, wherein in formula I, R1 either represents an unsubstituted alkyl group or an alkyl group substituted by an aryl group and/or each R2 represents a hydrogen atom.

12. An acid addition salt as claimed in claim 9, wherein R1 is a benzyl or substituted benzyl group.

13. An acid addition salt as claimed in claim 9 which is a sulfonic acid addition salt of 5-ALA methyl ester, 5-ALA hexyl ester, 5-ALA benzyl ester, 5-ALA 2-methylpentyl ester, 5-ALA 4-methylpentyl ester, 5-ALA 2-(2-ethoxyethoxy)ethyl ester, 5-ALA 4-methylbenzyl ester or 5-ALA 4-isopropylbenzyl ester.

14. An acid addition salt as claimed in claim 9 which is a sulfonic acid addition salt of 5-ALA methyl ester, 5-ALA hexyl ester or 5-ALA benzyl ester.

15. An acid addition salt as claimed in claim 13 or claim 14, wherein said acid is napthalene-1,5-disulfonic acid, ethane-1,2-disulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dodecylsulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethanesulfonic acid, or (+)-camphor-10-sulfonic acid.

16. An acid addition salt as claimed in of claim 1, wherein said acid is an inorganic acid.

17. An acid addition salt as claimed in claim 16, wherein said acid is sulfuric acid, nitric acid or phosphoric acid, preferably nitric acid.

18. An acid addition salt as claimed in claim 1, wherein said acid is a sulfonic acid, a sulfonic acid derivative or nitric acid.

19. An acid addition salt as claimed in claim 1, wherein said acid is pharmaceutically acceptable.

20. A process for preparing an acid addition salt as claimed in claim 1, said process comprising reacting a 5-aminolevulinic acid derivative with an acid as defined in claim 1.

21. A process for the preparation of an acid addition salt as claimed in claim 1, said process comprising the reaction of 5-aminolevulinic acid, or an esterifiable derivative thereof, with an alkanol or an ester-forming derivative thereof in the presence of an acid as defined in claim 1.

22. A process for the preparation of an acid addition salt as claimed in claim 1, said process comprising: (i) contacting a solution comprising a hydrochloride salt of an ALA derivative with a basic anion exchange resin;(ii) optionally removing said resin; and(iii) mixing the resulting solution with a solution comprising an acid as defined in claim 1.

23. A process for the preparation of an acid addition salt as claimed in claim 1, said process comprising: (i) reacting a hydrochloride salt of an ALA derivative with a silver salt of an acid as defined in claim 1, in a solvent in which AgCl is substantially insoluble; and(ii) optionally separating AgCl from the resulting salt.

24. An acid addition salt obtainable by contacting a 5-ALA derivative with an acid as defined in claim 1.

25. An acid addition salt obtainable by a process as claimed in claim 20.

26. A pharmaceutical composition comprising an acid addition salt as claimed in claim 1, together with at least one pharmaceutical carrier or excipient.

27. An acid addition salt as claimed in claim 1 or composition as claimed in claim 26, for use as a medicament.

28. (canceled)

29. A method of photochemotherapeutic treatment of disorders or abnormalities of external or internal surfaces of the body, said method comprising administering to the affected surfaces, an acid addition salt as claimed in claim 1 or composition as claimed in claim 26, and exposing said surfaces to light.

30. A product comprising an acid addition salt as claimed in claim 1, together with at least one surface-penetration assisting agent, and optionally one or more chelating agents as a combined preparation for simultaneous, separate or sequential use in treating disorders or abnormalities of external or internal surfaces of the body which are responsive to photochemotherapy.

31. A kit for use in photochemotherapy of disorders or abnormalities of external or internal surfaces of the body comprising: a) a first container containing an acid addition salt as claimed in claim 1,b) a second container containing at least one surface penetration assisting agent; and optionallyc) one or more chelating agents contained either within said first container or in a third container.

32. A method of in vitro diagnosis of abnormalities or disorders by assaying a sample of body fluid or tissue of a patient, said method comprising at least the following steps: i) admixing said body fluid or tissue with an acid addition salt as claimed in claim 1,ii) exposing said mixture to light,iii) ascertaining the level of fluorescence, andiv) comparing the level of fluorescence to control levels.

33. A method of treating a condition that is responsive to photochemotherapy comprising administering to an area of the body affected by said condition an acid addition salt as claimed in claim 1.

34. The acid addition salt as claimed in claim 1 wherein the 5-aminolevulinic acid derivative is a 5-ALA ester.

35. The acid addition salt as claimed in claim 1 wherein the acid has a pKa of about 3 or less.

36. An acid addition salt as claimed in claim 3, wherein R1 represents an unsubstituted C1-6 alkyl or a C1-2 alkyl substituted by an aryl group.

37. An acid addition salt as claimed in claim 35, wherein the C1-2 alkyl substituent is phenyl.

38. An acid addition salt as claimed in claim 9, wherein R represents an optionally substituted C1-20 alkyl group or an optionally substituted aryl group of up to 20 carbon atoms.

39. An acid addition salt as claimed in claim 11, wherein R1 represents an unsubstituted C1-6alkyl or a C1-2 alkyl substituted by an aryl group.

40. An acid addition salt as claimed in claim 38, wherein the C1-2 alkyl substituent is phenyl.

41. A process as claimed in claim 20, wherein the 5-aminolevulinic acid derivative is an ALA ester.

42. A process as claimed in claim 21, wherein the ester-forming derivative is an alkanol.

43. A process as claimed in claim 22, wherein the acid addition salt is a compound of formula I.

44. A process as claimed in claim 22, wherein the hydrochloride salt of an ALA derivative is a compound of the formula Cl−R22N+H—CH2COCH2CH2CO2R1, wherein R1 represents an optionally substituted straight-chained, branched or cyclic alkyl group which may optionally be interrupted by one or more —O—, —NR3—, —S— or —PR3— groups;R2 each independently represents a hydrogen atom or an optionally substituted straight-chained, branched or cyclic alkyl group which may optionally be interrupted by one or more —O—, —NR3—, —S— or —PR3— groups; andR3 is a hydrogen atom or a C1-6 alkyl group.

45. A process as claimed in claim 22, wherein in step (iii) the acid is a sulfonic acid or a sulfonic acid derivative.

46. A process as claimed in claim 23, wherein the acid addition salt is a compound of formula I.

47. A process as claimed in claim 23, wherein the hydrochloride salt of an ALA derivative is a compound of the formula Cl−R22N+H—CH2COCH2CH2CO2R1, wherein R1 represents an optionally substituted straight-chained, branched or cyclic alkyl group which may optionally be interrupted by one or more —O—, —NR3—, —S— or —PR3— groups;R2 each independently represents a hydrogen atom or an optionally substituted straight-chained, branched or cyclic alkyl group which may optionally be interrupted by one or more —O—, —NR3—, —S— or —PR3— groups; andR3 is a hydrogen atom or a C1-6 alkyl group.

48. A process as claimed in claim 23, wherein in step (i) the acid is a sulfonic acid or a sulfonic acid derivative.

49. An acid addition salt as recited in claim 24 wherein the ALA derivative is a 5-ALA ester.

50. The method of claim 29 wherein the light is white light, light in the wavelength region 300-800 nm, or blue light in the wavelength region 380-440 nm.