WO1994010345A1

WO1994010345A1 - Skin treatment

Info

Publication number: WO1994010345A1
Application number: PCT/GB1993/002178
Authority: WO
Inventors: David Greenwood; Jeremy Mark Holmes; Roderick Mcleod Webster
Original assignee: Zeneca Limited
Priority date: 1992-10-23
Filing date: 1993-10-22
Publication date: 1994-05-11
Also published as: AU5340594A; GB9222260D0

Abstract

Collagen is treated with a water-soluble compound which, in the free acid form, is of formula (1) wherein: L is an organic linking group; W is a covalent bond, -O-, -S-, -SO-, SO2-, -SO2NR?1-, -NR1-, -NR1CO(CH¿2)p-, -NR?1CONR1-, -NR1CH¿2CONR1-, -CONR1-, -CH=CH-, -(CH¿2?)p-, or (CH2)p-NR?1¿-; Y is a reactive group which comprises a heterocyclic reactive group, an activated vinyl group or a group convertible on treatment with aqueous alkali to an activated vinyl group, each R1 independently is H or C¿1-4?-alkyl; m and n each independently have a value of 0 or 1; and p has a value of 1 to 4; provided that when a compound of formula (1) has four or more carboxy groups its molecular weight is below 500.

Description

SKIN TREATMENT

THIS INVENTION relates to the process for the treatment of collagen, a process for tanning collagen and chemical compounds suitable for use in the processes.

It is known that collagen, the principal protein of animal skins and hides, may be converted to stable leather by tanning using a metal tannage containing Chromium, Aluminium, Titanium, Zirconium, Iron or Cerium salts. The metal tannages form molecular ion bridges crosstinking carboxy groups found in collagen to give stable leather.

I

Although known tanning processes are effective there is a need to improve the fixation of metals to collagen and leather. Preferably such a process should not reduce shrinkage temperature (Ts) or adversely affect swelling of resultant leather and the leather should remain stable to acid dyebath conditions.

Treatments involving the bonding of 1 ,2 carboxylic acids to collagen are disclosed in a paper by Evans et al, J.A.L.C.A. Vol 82 (1987) pages 88 to 95. Aluminium tannage of the modified collagen resulted in excessive swelling and reduced dye affinity.

According to the present invention there is provided a process for the treatment of collagen comprising applying thereto a water-soluble compound which, in the free acid form, is of Formula (1):

where

L is an organic linking group;

W is a covalent bond, -0-, -S-, -SO, -S0₂-, -SOjNR¹-, -NR¹-

-NR¹CO(CH₂)_p-, -NR¹CONR¹-, -NR'CH^ONR¹-, -CONR¹-, -CH =CH-, -(CH₂)P- or -

Y is a reactive group which comprises a heterocyclic reactive group, an activated vinyl group or a group convertible on treatment with aqueous alkali to an activated vinyl group. each R¹ independently is H or C^-alkyl;

SUBSTITUTE SHEET m and n each independently have a value of 0 or 1 ; and p has a value of 1 to 4; provided that when a compound of Formula (1 ) has four or more carboxy groups it molecular weight is below 500 and preferably below 450. The term activated means that an electron withdrawing group, for example S0₂, CO or C0₂, is attached to the vinyl group thereby rendering it susceptible to nucleophilic substitution.

As will be understood from the above proviso the present invention includes (a) compounds of Formula (1 ) which have four or more, for example 4 to 8, carboxy groups and a molecular weight below 500;

(b) compounds of Formula (1 ) having less than four, for example 0, 1 , 2 or 3, carboxy groups and a molecular weight equal to or above 500; and

(c) compounds of Formula (1) having less than four, for example 0, 1, 3 or 3, carboxy groups and a molecular weight below 500. All molecular weights refer to the compound in its free acid form. The preferred compounds are of type (b), more preferably type (c) as these are found to have particularly good properties.

It is believed that compounds of Formula (1 ) having a molecular weight below 500 are less likely to cause swelling of leather or collagen than heavier molecules and thus are particularly preferred. Swelling is undesirable because it leads to leather having a poor appearance, a rubbery texture and a loss in area.

R¹ is preferably H.

The compound of Formula (1) preferably has less than 4, more preferably less than 3 carboxy groups.

L preferably comprises from 1 to 3 groups selected from optionally substituted alkyl and optionally substituted aryl. In one embodiment L comprises two optionally substituted aryl groups connected by a group defined by W. In a second embodiment L comprises an optionally substituted aryl group or an optionally substituted aryl group connected to an optionally substituted alkyl group.

The preferred optionally substituted alkyl groups comprise a chain of from 1 to 6 carbon atoms optionally interrupted by a group defined above by W, especially an amido, amino, ether or thioether group. The preferred optionally substituted aryl group is optionally substituted phenγlene. The optional substituents which may be present in L are preferably selected from -OH, C,.,- alkγl, carboxy and sulpho. A preferred group represented by L contains from 4 to 14 carbon atoms.

Examples of groups represented by L include:

_/ ^{C H} ^^{~C H 2""} -^{C H}2-^C H-( ^C H₂ ⁰H )₃—CH₂-

wherein W is as hereinbefore defined.

The groups represented by W may be either way round, for example -

S0₂NR¹- includes - R'SOj-.

Examples of activated vinyl groups include -S0₂CH = CH₂,

-COCH = CH₂ and -OCOCH = CH₂. Examples of groups convertible on treatment with aqueous alkali to activated vinyl groups include -S0₂CH₂CH₂OS0₃H, -

S0₂CH₂CH₂SS0₃H, -S0₂CH₂CH₂C1 and -S0₂CH₂CH₂OCOCH₃.

The activated vinyl group or group convertible to an activated vinyl group is preferably attached to W through an alkγlene or arylene group, more preferably a C₂^-alkylene or phenγlene group. When Y is a heterocyclic group it preferably contains 1 , 2 or 3 nitrogen atoms in the heterocyclic ring and at least one labile atom or group on a carbon atoms of that ring. A labile atom or group is an atom or group which is displaceable by a nucleophile under alkaline conditions.

As examples of such heterocyclic reactive groups there may be mentioned:

2:3-dichloroquinoxaline-5- or -6-sulphonyl,

2:3-dichloroquinoxaline-5- or -6-carbonyl,

2:4-dichloroquinazolin-6- or -7-sulphonyl,

2:4:6-trichloroquinazolin-7- or -8-sulphonγl, 2:4:7- or 2:4:8-trichloroquinazolin-6-sulphonyl,

2:4-dichloroquinazolin-6-carbonyl,

1 :4-dichlorophthalazine-6-carbonyl,

4:5-dichloropyridazon-1-yl-ethylcarbonyl,

2:4-dichloropyrimidine-5-carbonyl, 4-(4':5'-dichloropyradaz-6'-on-1-yl)benzoyl,

2-chlorobenzthiazole-6-carbonyl,

3,6-dichloropyrazin-4-carbonyl, 4-(4':5'-dichloropyradaz-6'-on-1-yl)phenylsulphonyl activated 4,6-dihalopyridin-

2-yl and 2,6-dihalopγridin-6-yl groups such as:

3,4,5,6-tetrafluoropyridin-2-yl,

2,3,5,6-tetrafluoropyridin-4-yl, 2,4,6-trifluoro-3-cyanopyridin-4-yl,

2,5,6-trichloro-3-cyanopyridin-4-yl,

2,6-difluoro-3-cyano-5-chloropyridin-4-yl and more particularly triazinyl or pyrimidinyl groups.

Examples of particular pyrimidinyl groups especially Cl, Br or F, in at least one of the remaining 2-, 4- and 6-positions. The 5-position may carry one of a variety of substituents such as Cl or CN which are not normally labile but may enhance the reactivity of substituents in other positions of the pyrimidine ring. As specific examples of such pyrimidinyl groups there may be mentioned:

2 , 6-dichloropyrimidin-4-yl, 4,6-dichloropyrimidin-2-yl,

2, 5, 6-trichloropyrimidin-6-yl,

4,5,6-trichioropyrimidin-2-yl,

5-chloro-2-methylsulphonyl-6-methylpyrimidin-4-yl,

2-6-dichloro-5 = cyanopyrimidin-4-yl, 4,6-dichloro-5-cyanopyrimidin-2-yl,

2,6-difluoro-5-chloropyrimidin-6-yl

4,6-difluoro-5-chloropyrimidin-2-yl,

2,6-difluoro-5-cyanopyrimidin-2-yl,

4,6-difluror-5-cyanopyrimidin-2-yl. Examples of particular triazinyl groups are triazin-2-yl groups having a labile atom or group at one or both of the 40 and 6-positions. In this instance a wide range of labile atoms or groups are available such as activated arγloxy or various groups linked through a sulphur atom, e.g. S0₃H but the preferred labile atoms are F, Br and especially Cl. Preferred reactive groups include quaternary ammonium groups such as a tri-lower alkyl ammonium, e.g. (CH₃)₃N⁺- and pyridinium groups especially those derived from pyridine carboxylic acids in particular from nicotinic or isonicotinic acid.

The triazinyl groups having only one labile atom or group on the nucleus in the 4- or 6-position may have a non-labile substituent in the remaining 4- or 6- position. As examples of such non-labile substituents there may be mentioned alkyl or aryl thio groups, alkoxy or aryloxy groups and optionally substituted amino groups.

Preferred forms of these non-labile substituents include C^-alkoxy, C,^- alkylamino and optionally substituted phenyl amino groups.

Especially preferred optionally substituted phenγlamino groups have the formula:

wherein G is H, methyl, ethyl, sulphomethγl, beta-carboxy, beta-hydroxy- or beta-cyanoethyl and Y and X are each independently selected from H, COOH, S0₃H, CH₃, C₂H₆, OCH₃, OC₂H_B, Cl, CN, NOC₂, NHC0CH₃ and beta- sulphatoethylsulphonyl .

A particularly preferred water-soluble compound suitable for use in the process is of Formula (2) or a salt thereof:

wherein: R\ m and n are as hereinbefore defined;

X is Cl, F or a quaternary ammonium group as hereinbefore defined; and G is HOCH₂(CHOH)«CH₂- or a group of Formula (3) or (4):

( 3 ) ( 4 ) A further preferred water-soluble compound is of Formula (5), (6) or (7):

G - N R ^, C 0 ( C H ₂ ) ₀ -V

( 7 ) wherein G, W, P and each R¹ are as hereinbefore defined and V is an activated vinyl group or a group convertible to an activated vinyl group on treatment with aqueous alkali as described hereabove.

The compounds of Formula (1) may be prepared by condensation of a compound of Formula (8) and a compound having at least two labile atoms or groups:

wherein W¹ i

and n are as hereinbefore defined. The condensation is preferably performed at a pH of 2 to 8, especially 6 to 7. A temperature of between -5°C and + 10°C, especially 0°C and + 5°C is preferred. For convenience the condensation is preferably performed in water.

As examples of compounds having at least two labile atoms or groups there may be mentioned the chlorides and fluorides of the above described heterocyclic reactive groups.

Compounds of Formula (1) which contain an amide link may be prepared by condensing together an appropriate amine and acid chloride, preferably under alkaline conditions. Compounds where W is -SO- or -S0₂- may be prepared by the above condensation wherein W¹ is thio followed by oxidation of the resultant thioether to -SO- or -S0₂- as desired.

The water-soluble compound is preferably applied to collagen at a temperature between 10°C and 40 °C, more preferably 20 °C and 30 °C, especially 23°C and 27°C. The preferred pH is between 6.5 and 12, especially 7 and 9.

The water-soluble compound is preferably applied to collagen as an aqueous solution in a weight ratio (relative to the weight of collagen) of 0.5:100 to 10:100, more preferably 2:100 to 5:100. The aqueous solution is preferably in contact with the collagen for 10 minutes to 24 hours, more preferably 30 minutes to 16 hours. Salt may be used to facilitate diffusion of the water- soluble compound into collagen, preferably in a weight ratio of 5:100 to 10:100 relative to collagen.

According to a further feature of the present invention there is provided a process for tanning collagen comprising the steps of (a) applying a water- soluble compound for Formula (1 ) to the collagen, and (b) applying a metal tannage to the product of step (a).

The water-soluble compound of Formula (1 ) used in step (a) is preferably applied by the method described hereabove. In step (b) the metal tannage may be applied at a variety of pHs depending upon the nature of tannage. Generally a pH from 0.5 to 5 and temperature of 20°C to 40°C is used. For titanium/aluminium tannages a preferred pH is from 1 to 5, more preferably 2.5 to 4.5. For zirconium tannages preferred pH is from 0.5 to 4, more preferably 1 to 3. The weight ratio of metal tannage to collagen preferably lies in the range 0.1 % to 20% as oxides

(calculated as the notional weight of metal oxide to leather as is customary in the art), more preferably 1 % to 10% as oxides.

Preferred metal tannages comprise water-soluble salts of Chromium III, Aluminium III, Titanium IV, Zirconium IV, Iron III, Cerium III, Cerium IV and mixtures thereof. Particularly preferred metal tannages are zirconium sulphate and the mixed titanium/aluminium tannages described in European Patent No 290,143.

The processes described herein may be performed on all types of collagen, particularly bovine, ovine, goat, deer and buffalo hides and amphibian, fish and reptilian skins.

Use of compounds of Formula (1) for the treatment of collagen and collagen treated with compounds of Formula (1) are further features of the invention. The compounds are preferably used in the manner described above. The processes for treating collagen according to the present invention are notable for improving the fixation of metal tannages. The shrinkage temperature of resultant leather is generally improved without adverse swelling and dyebath stability under acidic conditions is also good. Although chemical formulae in this specification have been represented in their free acid form it will be understood that the formulae also include salt form, for example alkali metal and ammonium salts, particularly sodium, potassium and lithium salts and mixtures thereof. The invention is further illustrated but not limited by the following examples in which all parts and percentages are by weight unless stated otherwise.

Example 1 - Preparation of Reactive Compounds

(a) Preparation of 2-(3',5'-dicarboxyphenyl amino)-4,6-dichloro-s-triazine (Reactive A)

3-5-Dicarboxyaniline (7.24 gm, 0.04 mol) was dissolved in distilled water (55ml) at room temperature, and cooled to 0-5 °C in an ice-water bath. To the resultant solution was added a solution of cyanuric chloride (7.71 g, 0.042 mol) in acetone (50ml) dropwise with stirring. The temperature was maintained at 0-5 °C throughout the addition, and the pH maintained at 6-7 by slow addition of a solution of sodium carbonate (1 ). As the reaction progressed, a pale coloured precipitate was produced. The suspension was stirred at 0-5 °C, pH 7 for a further 1 hour after complete addition of the cyanuric chloride. This suspension was filtered off and the filtrate washed with mixed phosphate buffer (2g of a 2:1 mixture of potassium dihydrogen orthophosphate: disodium hydrogen orthophosphate). The filtrate was pulled dry, washed with acetone (to remove any unreacted cyanuric chloride) and dried in vacuo overnight to give 10.8g of Reactive A. Infra red analysis of Reactive A (KBr disc) showed peaks at 3286, 3177, 1614 and 857cm'¹. (b) Preparation of 2-(3'-hydroxy-4'-carboxyphenyl amino)-4,6- dichloro- triazine (Reactive B)

The method of Example 1 , stage (a) was followed except that in place of 3,5-dicarboxyaniline there was used an equivalent amount of 3-hydroxy-4- carboxyaniline. Infra red analysis of Reactive B showed peaks at 3290, 3160, 1625 and

855cm ¹.

(c) Preparation of 2-(3',4'-dicarboxypheny amino)-4,6-dichloro-s-triazine

(Reactive C)

The method of Example 1 , stage (a) was followed except that in place of 3,5-dicarboxγaniline there was used an equivalent amount of 3,4- dicarboxγxaniline .

Infra red analysis of Reactive C showed peaks at 3280, 3190, 1620 and 850cm ¹.

(d) Preparation of Reactive D of the Formula

The method of Example 1 , stage (a) was followed except that in place of 3,5-dicarboxyaniline there was used an equivalent amount of 4-aminomandelic acid.

Infra red analysis of Reactive D showed peaks at 330, 3150, 1613 and 849m-¹.

(e) Preparation of Reactive E of the formula

The method of Example 1 , stage (a) was followed except that in place of 3,5-dicarboxyaniline there was used an equivalent amount of N-methyglucamine. Infra red analysis of Reactive E showed peaks at 330 and 846cm^'1.

Example 2 • General Method a) Pre-treatment with Reactive Compound

Bovine hide powder (5.5g, SLTC Official Hide Powder available from the British Leather Confederation) was suspended in distilled water (20ml) to remoisturise it. A solution of a Reactive compound (2.75g in 55ml of distilled water) was added to the suspension of hide powder and the mixture shaken for 30 minutes in a sealed jar. To facilitate diffusion of the Reactive compound into the hide a solution of NaCI was added to give an 8% salt solution by weight and shaking was continued for 24 hours. After 24 hours shaking, the Reactive compound was fixed to the hide powder by raising the pH from 6 to 9 by addition of IN NaOH solution. Shaking was continued for a further 1 hour. The resultant suspension was acidified to pH 3 using IN HCI and the solids filtered off onto glass-fibre filter paper, washed with water, brine, water to give treated hide powder. b) Tanning

The treated hide powder from a) above was suspended in water (20ml) and 55ml of a 10% solution of Tanning Agent A was added (Tanning Agent A comprises by weight aluminium sulphate (45%), titanyl sulphate (18.5%), dolomite (20%), sodium gluconate (14%) and the balance water). The resultant mixture was shaken at room temperature for 72 hours then basified to pH 4 by addition of 1N Na,C0₃ over about 30 minutes. The hide powder was filtered off, washed successively with water, brine, water and dried to give a solid tanned hide powder. c) Assessment of Shrinkage Temperatures

The shrinkage temperature of the treated hide powder from step a) and the tanned hide powder from b) were assessed by measuring the 'peak temperature', that is to say the temperature at which the leather deforms or denatures. The correlation between peak temperature and hide powder and shrinkage temperature of hide is well established in the art, see for example J.A.L.C.A., 6J_, 64 (1966) and J.A.L.C.A., 8J., 213 (1986).

The hide powder from steps a) and b) above was re-hydrated by addition of water and a sample of each (approximately 100mg, accurately weighed) was placed into a standard aluminium vessel. The vessel was sealed and then heated such that the temperature increased in 5°C steps and the resultant endotherm measured on a Differential Scanning Colorimeter using the standard protocol supplied with the instrument. The temperature at which the endotherm was greatest is referred to as the peak temperature. d) Results

To assess the effect concentration of the tanning agent had on peak temperatures the method described under b) above was repeated using 55ml of 1 % Tanning Agent A in place of the 10% solution. As a control peak temperatures were also measured for hide powder which had not been treated with a Reactive compound.

Table 1 below shows the peak temperatures for untanned hide powder after treatment with Reactives A to D (column I), hide powder after tanning with a 1 % solution of Tanning Agent A (column II) and hide powder after tanning with 10% solution of Tanning Agent A (column III). Table 1

Where two figures are quoted in a column of Table 1 these represent the results of two experiments. * signifies not measured.

From Table 1 it can be seen that treatment with Reactive A to D improves the peak temperature and therefore shrinkage temperature of leather. Little or no swelling of the leather was observed. Example 3 a) Pre-treatment with Reactive A

A 50g piece of fellmongered pickled sheepskin pelt was placed in a first drum (dimensions 30cm diameter, 16cm deep, horizontal axis) together with 50ml of a 10% w/v aqueous salt solution. The pH was adjusted using solid sodium bicarbonate to pH 9.5 and 2.5g of Reactive A was added to the liquor in the drum. The drum was rotated overnight. A second drum was prepared in an identical manner except that Reactive A was omitted. The pelt in the second drum is referred to as the control. b) Tanning

After the overnight treatment, the liquor from each drum was allowed to drain off, the pelt was rinsed in aqueous 10% w/v salt solution and the pH of the pelt adjusted to 1.5 using dilute sulphuric acid in fresh 10% NaCI solution. Each piece of pelt was then placed in a drum and immersed in 50ml of Tanning Agent B comprising:

0.8g titanium sulphate TiOS0₄.2H₂0

2.7g aluminium sulphate AI₂(S0₄)₃.16H₂0

2.5g magnesium sulphate MgS0₄.7H₂0

0.65g sodium gluconate 2.67g finely divided dolomite 4.0g sodium chloride the balance water The drum was rotated overnight and then each piece was gradually basified to pH 4.5 using solid sodium bicarbonate, c) Results

The tanned pelts (i.e. leather) were removed from the drum and the shrinkage temperature (hydrothermal stability) measured by the standard method SLT18:BS3144:1966 of the Society for Leather Technicians. The shrinkage temperatures (Ts) for the leather which had been pre- treated with Reactive A (derived from the first drum) was 57.5 °C before tannage and 96°C after tannage. For the control piece (derived from the second drum) the corresponding Ts values were 54°C and 79.5°C. Thus pretreatment with Reactive A caused the Ts of tanned leather to rise from 79.5°C to 96°C.

There was no evidence of excessive swelling in the leather which had been pre-treated with Reactive A and after dyeing, fat liquoring and drying the leather was softer than the control piece.

Compared with the control leather (which gelatinised) the leather pre- treated with Reactive A was found to have much greater dyebath stability.

Dyebath stability was assessed by immersing leather in water at pH 3 and 60°C for 6 hours; conditions chosen to represent the most severe that are likely to be encountered in industrial practice. Example 4 a) Pre-treatment with Reactive E

The method of Example 3, part a), was followed except that in place of Reactive A there was used an equivalent amount of Reactive E and the pH used was pH 9 for 5 hours then overnight at pH 9.5. b) Tanning Each piece of pre-treated pelt was divided into 3 for tannage with one of the following at a liquor to pelt ratio of 1 :1 (by weight): (i) Tanning Agent B described in Example 3, part b);

(ii) A 7.5% w/v solution of Zr(S0₄)₂.H₂0 with basification to pH 2.7 using sodium bicarbonate; (iii) A 7% w/v aqueous solution of Ti0S0₄.2H₂0 with basification to pH 4 using sodium bicarbonate. c) Results

The shrinkage temperature for untreated and pre-treated leathers before and after tanning were as shown in Table 2: Table 2

From Table 2 it can be clearly seen that pre-treatment with Reactive E increases the shrinkage temperature of leather tanned by Zr, Ti.

Compared with the untreated leathers it was found that leathers pre- treated with Reactive E were softer after dyeing, fat liquoring and drying and maintained their Ts values after the dyebath stability test. Example 5 a) Pre-treatment with Reactive B

The method of Example 4, part a), was followed except that in place of Reactive E there was used an equivalent amount of Reactive B. b) Tanning

Each pelt was divided into three pieces and tanned as described in Example 4, part b). c) Results Each shrinkage temperature for untreated and pre-treated leathers before and after tanning are shown in Table 3:

Table 3

From Table 3 it can clearly seen that the shrinkage temperature has been increased by pre-treatment with Reactive B, particularly for Ti and Al and Ti tannages.

Compared with the untreated leathers the leather pre-treated with Reactive B was softer and maintain its Ts value after the dyebath stability test.

93TJL1 1 S.WP5 - MS 21 Oct 1993

Claims

1 A process for the treatment of collagen comprising applying thereto a water-soluble compound which, in the free acid form, is of Formula (1 ):

wherein:

L is an organic linking group;

W is a covalent bond, -0-, -S-, -SO-, -S0₂-, -SOzNR¹-, -NR¹-,

-(CH₂)_P-, or (CH^-NR¹-;

Y is a reactive group which comprises a heterocyclic reactive group, an activated vinyl group or a group convertible on treatment with aqueous alkali to an activated vinyl group. each R¹ independently is H or C^-alkyl; m and n each independently have a value of 0 of 1 ; and p has a value of 1 to 4; provided that when a compound of Formula (1) has four or more carboxy groups its molecular weight is below 500.

2 A compound of Formula (2) or a salt thereof:

wherein: R¹ is H or C-₄-alkyl;

X is Cl, Br, F or a quaternary ammonium group; and G is HOCH₂(CHOH)₄CH₂- or a group of Formula (3) or (4):

( 3 )

( 4 )

A compound of the Formula (5), (6) or (7)

C H ₂ C H₂ - V ) ₂

( 5 )

( 7 ) wherein:

P has a value of 1 to 4;

W is as defined in Claim 1 ;

G and R¹ are as defined in Claim 2; and

V is an activated vinyl group of a group convertible to an activated vinyl group on treatment with aqueous alkali.

4 A process of treatment of collagen which comprises applying thereto a water soluble compound as claimed in Claim 2 or 3.

5 A process for tanning collagen comprising the steps of (a) applying a water-soluble compound of Formula (1 ) as defined in Claim 1 to the collagen, and (b) applying a metal tannage to the product of step (a).

6 A process as claimed in Claim 5 in which the metal tannage is effected with Chromium III, Aluminium III, Titanium IV, Zirconium IV, Iron III, Cerium III and/or Cerium IV ions.

7 A process as claimed in Claim 5 or 6 in which the metal tannage is effected with zirconium sulphate.

8 A process as claimed in Claim 5 or 6 in which the metal tannage is effected with a mixed titanium/aluminium tannage.

9 Leather which comprises metal ion bonding sites derived by reacting a compound of formula (1 ) with collagen.

10 Leather as claimed in Claim 9 which comprises tanning metal ions bonded to the said sites.

1 1 A process of making a compound according to Claim 2 in which a compound of formula

G - N - H is reacted with R¹ cyanic chloride, bromide or iodide.