HUP0101104A2 - Process for preparing resorcinol derivatives - Google Patents

Abstract

Preparation of 4-substituted resorcinol derivatives (I) or (II) comprises reacting 1-alkoxy or hydroxy-6-halo-3-substituted-2-oxabicyclo(2.2.2)octane-5-one (II) or 4-substituted-2-halo-cyclohexan-1,3-dione (III) with a base. Process (A) for the preparation of 4-substituted resorcinol derivatives of formulae (I) or (II) comprises reacting 1-alkoxy or hydroxy-6-halo-3-substituted-2-oxabicyclo(2.2.2)octane-5-one of formula (II) or 4-substituted-2-halo-cyclohexan-1,3-dione of formula (III) with a base. [Image] W : H or protecting group; X, Y : 1-12C alkyl, 2-12C alkenyl or 2-12C alkynyl (all optionally substituted by 1-3 Z) or H, or CXY : 4-8C cycloalkyl or 5-8C cycloalkenyl ring (both optionally substituted by Z), provided that the 4-8C cycloalkyl ring or 5-8C cycloalkenyl ring is not aromatic; Z : CN, halo, 1-6C alkyl, aryl, 2-9C heterocycloalkyl, 2-9C heteroaryl, aryl-(1-6C)alkyl, =O, =CHO(1-6C) alkyl, NH 2, OH, 1-6C alkoxy, aryl-(1-6C)alkoxy, 1-6C acyl, 1-6C alkylamino, aryl (1-6C) alkylamino, amino(1-6C) alkyl, 1-6C alkoxy-CO-NH-, 1-6C alkylamino-CO-, 2-6C alkenyl, 2-6C alkynyl, OH-(1-6C)alkyl, 1-6C alkoxy-(1-6C)alkyl, 1-6C acyloxy-(1-6C)alkyl, NO 2, cyano-(1-6C)alkyl, halo-(1-6C)alkyl, nitro(1-6C)alkyl, trifluoromethyl, trifluoromethyl-(1-6C)alkyl, 1-6C acylamino, (1-6C)acyl amino (1-6C)alkyl, 1-6C alkoxy-(1-6C)acylamino, amino(1-6C)acyl, amino-(1-6C)acyl-(1-6C)alkyl, 1-6C alkylamino-(1-6C)acyl, (1-6C alkyl) 2-amino(1-6C)acyl, -CO 2R 2>, 1-6C alkyl-CO 2R 2>, -C(O)N(R 2>) 2, 1-6C alkyl-C(O)N(R 2>) 2, R 2>ON=, R 2>ON=(1-6C)alkyl, R 2>ON=CR 2>(1-6C)alkyl, NR 2>(OR 2>), 1-6C alkyl-NR 2>(OR 2>), -C(O)(NR 2>OR 2>), 1-6C alkyl-C(O)(NR 2>OR 2>), S(O) mR 2>, R 3>C(O )O-, R 3>C(O)O-(1-6C)alkyl, R 4>R 5>N-C(O)O-, R 4>R 5>NS(O) 2, R 4>R 5>NS(O) 2 (1-6C)alkyl, R 4>S(O) 2R 5>N, R 4>S(O) 2R 5>N-(1-6C)alkyl, -C(=NR 6>)(N(R 4>) 2), -(1-6C)alkyl-C(=NR 6>)(N(R 4>) 2), -OC(O)aryl (1-6C)alkyl, NH(1-6C)alkyl, aryl-1-6C alkyl-HN or a ketal; R 3>1-6C alkyl, aryl or aryl-1-6C alkyl; R 2>H or R 3>; R 4>, R 5>H or 1-6C alkyl; R 6>OR 2> or R 2>; m : 0-2, and Q : halo. Independent claims are also included for the following: (1) preparation of (III; W = a protecting group) which comprises reacting a ketone compound of formula (V) with a halogenating agent; (2) preparation of (IV) which comprises reacting (V) with a halogenating agent; (3) preparation of (V) which comprises reacting a ketone compound of formula (VI) with O=CXY in the presence of base; (4) preparation of resorcinol derivatives of formula (VII) which comprises the process (A) as above and reducing (I; W = H) or (II; W = H) or reducing (I; W = protecting group) or (II; W = protecting group) and removing the protecting group; (5) preparation of (VII) which comprises process (A) as above to give (I), reacting (I) with a base to give (II) and hydrogenating (II; W = H), or removing the protecting group from (II; W = protecting group) and hydrogenating the obtained (II; W = H); (6) preparation of (VII) which comprises process (A) as above to give (II) and hydrogenating (II; W = H), or removing the protecting group from (II; W = protecting group) and hydrogenating the obtained (II; W = H); (7) preparation of (II; W = H) as in (5) or (6), and (8) new compounds (V), (III) and (IV). [Image] ACTIVITY : Dermatological. MECHANISM OF ACTION : None given.

Description

P 010 110 4 -/. .: : . ··/···;

72.105/SZE 'Y/tefT ' ns ^τ 'θΉ Hv/ i I \,i _t i,sy ut 113.

Process for the preparation of resorcinol derivatives

The present invention relates to an improved process for the preparation of 4-substituted resorcinol derivatives.

Resorcinol derivatives are known to have many uses. For example, in cosmetics they can be used to lighten skin color. The use of resorcinol derivatives as skin lightening agents is described, for example, in European Patent Application EP 904 774 (published March 31, 1999), U.S. Patent No. 5,468,472 (issued November 21, 1995), U.S. Patent No. 5,399,785 (issued March 21, 1995), European Patent Application EP 623 339 (published November 9, 1994), Japanese Patent No. JP 5-4905 (published January 14, 1993) and European Patent Application EP 341 664 (published November 15, 1989).

Resorcinol derivatives are used as antidandruff agents (JP Patent No. 4-169,516, published June 17, 1992), antiacne agents (JP Patent No. 4-169511, published June 17, 1992), as enhancers of antimicrobial compounds (U.S. Patent No. 4,474,748, issued October 2, 1984), and as antibrowning agents for foods (U.S. Patent No. 5,304,679, published April 1994).

19) and in the production of photographic color images (United States Patent No. 3,756,818, issued September 4, 1973).

The present invention provides an improved process for the preparation of 4-substituted resorcinol derivatives. The present invention also provides intermediates that can be used in the preparation of such resorcinol derivatives. The process of the present invention provides a simpler process for the preparation of resorcinol derivatives in large quantities than the methods used heretofore. Furthermore, the improved process of the present invention provides the final product in higher yield than the methods used heretofore.

The invention relates to a process for the preparation of resorcinol derivatives of the general formula (I) and their pharmaceutically acceptable salts, wherein in the general formula (I) the dashed line optionally represents a double bond;

X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl or C5-C8 cycloalkenyl group is not aromatic; said C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C4-C8 cycloalkyl and C5-C8 cycloalkenyl groups are optionally substituted with 1-3 Z groups, wherein Z can be any substituent that enables the preparation of the given substituted resorcinol derivative according to the present invention.

In a preferred embodiment of the process according to the invention, Z is cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)- ·: .: : — :···:

(C1-6)-alkoxy, (C1-6)-acyl, (C1-6)-alkylamino, (C1-6)-aryl-(C1-6)-alkylamino, (C1-6)-aminoalkyl, (C1-6)-alkoxy-CO-NH-, (C1-6)-alkylamino-CO-, (C2-6)-alkenyl, (C2-6)-alkynyl, (C1-6)-hydroxyalkyl, (C1-6)-alkoxy(C1-6)-alkyl, (C1-6)-acyloxy-(C1-6)-alkyl, nitro, cyano-(C1-6)-alkyl, halogenated (C1-6)-alkyl, (C1-6)-nitroalkyl, trifluoromethyl, trifluoromethyl-(C1-6)- carbon)-alkyl-, C1-6 acylamino-, C1-6 acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acylamino-, C1-6 aminoacyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkylamino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl group, -CO ₂ R ² , -(C1-6 alkyl)-CO2R ² , C(O)N(R ² )2, -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(1-6 groups of the general formula R ² , wherein R 2 is independently hydrogen, ^{C 16} alkyl, ^aryl or aryl-(C ^{1-6 )} -alkyl ^{; R 3 is} a group ^{of the general formula C(O)O-, where R 3 is C} 1-6 alkyl, aryl or aryl-(C ^1-6 )-alkyl ^; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O)2-, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ )2), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- or ketal.

—·. .: : ·.·:··.;

* · · · · .

*· ·,,·········»«

The present invention also provides various compounds which can be used in the process of the invention. The invention also extends to the preparation of these intermediates. More particularly, the invention relates to a process for the preparation of a compound of formula (6) - wherein W represents a hydrogen atom or a protecting group; X and Y are independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-8 cycloalkyl or C5-8 cycloalkenyl group, provided that the C4-8 cycloalkyl and the C5-8 cycloalkenyl groups are non-aromatic, and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and the C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z groups as defined above. to obtain a compound of formula Q is preferably bromine, iodine or chlorine, more preferably bromine or iodine, most preferably bromine.

The invention further provides a process for preparing a compound of formula (7) wherein W, X and Y are as defined above, which comprises reacting a compound of formula (5) wherein Q is as defined above with a base to obtain the compound of formula (7).

In a preferred embodiment, the compound of formula (5) is prepared by reacting a compound of formula (4) wherein W, X and Y are as defined above with a halogenating agent, wherein Q is the halogen atom in the compound of formula (5). In a preferred embodiment, Q is bromine, i.e., the compound of formula (4) is reacted with a brominating agent, such as N-bromosuccinimide.

⁵ ·: · . ··?

In a further preferred embodiment, the compound of formula (4) is prepared by reacting a compound of formula (2) with a compound of formula (3) in the presence of a base. In the formulae, W, X and Y are as defined above.

The present invention further provides a process for preparing a compound of formula (5) wherein Q, W, X and Y are as defined above, which comprises reacting a compound of formula (4) with a halogenating agent as described above to obtain a compound of formula (5).

In a preferred embodiment, the compound of formula (4) is prepared by reacting a compound of formula (2) with a compound of formula (3) to obtain the compound of formula (4). In the formulae, W, W and Y are as defined above.

The present invention further provides a process for preparing a compound of formula (4) wherein W, X and Y are as defined above, which comprises reacting a compound of formula (2) with a compound of formula (3) in the presence of a base.

The present invention further provides a process for preparing a compound of formula (Ia) wherein X and Y are as defined above, which comprises (a) reacting a compound of formula (5) wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above with a base to obtain a compound of formula (6); and (b) wherein W is a hydrogen atom, reducing the compound of formula (6) to obtain a compound of formula (Ia); or (c) wherein W is a protecting group, reducing the compound of formula (6) thus obtained and removing the protecting group to obtain a compound of formula (Ia).

♦·········.<

In a preferred embodiment, the compound of general formula (6) is converted to the compound of general formula (Ia) by reaction with triethylsilane in the presence of tefyl-ewis acid or by hydrogenation under conventional conditions.

The present invention further provides a process for preparing a compound of formula (Ia) wherein X and Y are as defined above, which comprises (a) reacting a compound of formula (5) wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above with a base to give a compound of formula (7); and (b) where W is a hydrogen atom, hydrogenating the compound of formula (7) thus obtained to give a compound of formula (Ia); or (c) where W is a protecting group, hydrogenating the compound of formula (7) thus obtained and removing the protecting group.

The invention further provides a process for the preparation of a compound of formula (Ia) - where X and Y are as defined above - which comprises (a) reacting a compound of formula (5) - where Q is a halogen atom, W is a hydrogen atom or a protecting group, X and Y are as defined above - with a base to obtain a compound of formula (6); and (b) reacting the compound of formula (6) thus obtained with a base to obtain a compound of formula (7); and (c) where W is a hydrogen atom, hydrogenating the compound of formula (7) thus obtained to obtain a compound of formula (Ia); or (d) where W is a protecting group, hydrogenating the compound of formula (7) thus obtained and removing the protecting group to obtain a compound of formula (Ia).

The present invention further provides a process for preparing a compound of formula (Ia) wherein X and Y are as defined above, which comprises (a) reacting a compound of formula (5) wherein Q is a halogen atom, w is a hydrogen atom or a protecting group, and X and Y are as defined above with a base to obtain a compound of formula (6); and (b) reacting the compound of formula (6) thus obtained with a base to obtain a compound of formula (7); and (c) hydrogenating the compound of formula (7) thus obtained where W is a hydrogen atom to obtain a compound of formula (Ia); or (d) where W is a protecting group, the compound of formula (7) thus obtained is deprotected to give the compound of formula (Ib), and the compound of formula (Ib) thus obtained is hydrogenated to produce the compound of formula (Ia).

The present invention further provides a process for preparing a compound of formula (Ia) wherein X and Y are as defined above, which comprises (a) reacting a compound of formula (5) wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above with a base to obtain a compound of formula (7); and (b) wherein W is a hydrogen atom, hydrogenating the compound of formula (7) thus obtained to obtain a compound of formula (Ia); or (c) wherein W is a protecting group, deprotecting the compound of formula (7) thus obtained to obtain a compound of formula (Ib), and hydrogenating the compound of formula (Ib) thus obtained to obtain a compound of formula (Ia).

The present invention further provides a process for preparing a compound of formula (Ib) wherein X and Y are as defined above, which comprises (a) reacting a compound of formula (5) wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above with a base to obtain a compound of formula (6), (b) reacting the thus obtained compound of formula (6) with a base to obtain a compound of formula (Ib) when W is a hydrogen atom or a compound of formula (7) when W is a protecting group; and (c) when W is a protecting group, removing the protecting group from the compound of formula (7) to obtain a compound of formula (Ib)

The present invention further provides a process for preparing a compound of formula (Ib) wherein X and Y are as defined above, which comprises (a) reacting a compound of formula (5) wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above with a base to obtain a compound of formula (Ib) when W is a hydrogen atom or to obtain a compound of formula (7) when W is a protecting group; and (b) when W is a protecting group, removing the protecting group from the compound of formula (7) thus obtained to obtain a compound of formula (Ib).

As described below in the description of the reaction process of Figure 1, the compound of formula (5), when W is hydrogen, is in equilibrium with the compound of formula (5'). In this case, the compound of formula (5') can be directly formed from the compound of formula (4). In all the processes described herein where the compound of formula (5) is used and where W is hydrogen, the compound of formula (5') can be used instead, under the same conditions; for example, in the preparation of the compounds of formula (6) or (7). The present invention also provides a process for the preparation of the compound of formula (5'), which comprises converting the compound of formula (4) - where W is hydrogen - to the compound of formula (5') with a halogenating agent.

The various methods described above are summarized in Figure 1.

In a preferred, non-limiting embodiment, X and Ϋ together with the substituent to which they are attached may form a C5-8 cycloalkyl or C5-8 cycloalkenyl group, which groups may be represented by the general formula (13) where n is 0, 1, 2 or 3. The C5-8 cycloalkyl ring or C5-8 cycloalkenyl ring is optionally substituted. In the general formula (13), the dashed line optionally represents a double bond at the indicated position. In a non-limiting embodiment, the C5-8 cycloalkyl group or C5-8 cycloalkenyl group is optionally substituted with 1-3 Z groups as defined above.

In one preferred embodiment, X and Y, together with the carbon atom to which they are attached, form a cyclohexyl or cyclohexenyl group, with cyclohexyl being more preferred.

In another preferred embodiment, X and Y, together with the carbon atom to which they are attached, form a cyclopentyl or cyclopentenyl group, of which cyclopentyl is more preferred.

In a further preferred embodiment, the C5-8 cycloalkyl or C5-8 cycloalkenyl group is unsubstituted.

In a further embodiment, the C5-8 cycloalkyl or C5-8 cycloalkenyl group is monosubstituted. More preferably, X and Y, together with the carbon atom to which they are attached, form a monosubstituted cyclohexyl or monosubstituted cyclopentyl group.

In a further preferred embodiment, the C5-8 cycloalkyl or C5-8 cycloalkenyl group is disubstituted. More preferably, X and Y, together with the carbon atom to which they are attached, form a disubstituted cyclohexyl group or a disubstituted cyclopentyl group.

·’·: .: : .........

ι* ·*·’***·

Where X and Y together with the carbon atom to which they are attached form a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3-position, more preferably at the 4-position.

Where X and Y together with the carbon atom to which they are attached form a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-position.

In a further preferred embodiment, X and Y, together with the carbon atom to which they are attached, form a group of general formula (13) substituted 1-3 times independently with the substituent Z as defined above, and wherein n is 0, 1 or 2.

In a further preferred embodiment, n is 0 or 1.

In a further preferred embodiment, n is 0 and the dashed line represents a double bond at that location.

In a further preferred embodiment, n is 1.

In a further preferred embodiment, the ring formed by X, Y and the carbon atom to which they are attached is substituted with OH, =O, =NOH, CH ₂ OH or a group or combination of groups of formula (14).

In a further preferred embodiment, n is 0, the ring formed by X, Y and the carbon atom to which they are attached is substituted with a group of the formula =NOH, and the dashed line represents a double bond at the indicated position.

In a further preferred embodiment, n is 1 and the ring formed by X, Y and the carbon atom to which they are attached is substituted with OH, =O, =NOH, CH ₂ OH or a group of formula (14) or a combination of groups.

Where Z is a heterocyclic cycloalkyl group of 2-9 carbon atoms, it is preferably a group of formula (15) where m is 0, 1 or 2 and Q is CH ₂ , NR ² , O, S, SO or SO ₂ .

In a further preferred embodiment, X and Y together with the carbon atom to which they are attached form a cyclohexyl, cyclohexenyl, cyclopentyl or cyclopentenyl group, which is singly substituted with a Z substituent which is OH, R ³ C(O)O-, R ³ C(O)-O-(C1-6)alkyl-, R ² ON=, R ² ON=(C1-6)alkyl-, R ² ON=CR ² (C1-6)alkyl-, -NR ² (OR ² ), R ⁴ S(O)2R ⁵ N- or R ⁴ S(O)2R ⁵ N(C1-6)alkyl-, or a group of the general formula, wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.

In a further preferred embodiment, X and Y together with the carbon atom to which they are attached form a cyclohexyl or cyclopentyl group, which is singly substituted with a Z substituent, which is OH, R ³ C(O)O-, R ³ C(O)-O(C1-6)alkyl-, R ² ON=, R ² ON=(C1-6)alkyl-, R ² ON=CR ² (C1-6)alkyl-, -NR ² (OR ² ), R ⁴ S(O)2R ⁵ N- or R ⁴ S(O)2R ⁵ N- (C1-6)alkyl-, or a group of the general formula, wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.

In a further embodiment, Z is hydroxyl.

In a further preferred embodiment, Z is a group of the general formula R ³ C(O)O-.

In a further preferred embodiment, Z is a group of the general formula R ³ C(O)-(1-6C)-alkyl-.

In a further preferred embodiment, Z is a group of the general formula R ² ON=, R ² ON=(C 1-6 )-alkyl- or R ² ON=CR ² (C 1-6 )-alkyl-.

In a further preferred embodiment, Z is a group of the general formula R ² ON=.

In a further preferred embodiment, Z is a group of the general formula -NR ² (OR ² ).

In a further preferred embodiment, Z is a group of the general formula F$ ⁴ S(Ö)2R ⁵ *Nf-.

In a further preferred embodiment, Z is a group of the general formula R ⁴ S(O) 2 R ⁵ N(C 1-6 )-alkyl-.

The process of the present invention can be used to prepare the following compounds, but is not limited to those listed.

4-cyclohexylresorcinol;

4-cyclopentylresorcinol;

4-(2,4-dihydroxyphenyl)cyclohexanol;

4-(2,4-dihydroxyphenyl)cyclohexanone;

4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

O-methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

O-benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-dihydroxyphenyl)-2-cyclohexen-1-one;

(+)-3-(2,4-dihydroxyphenyl)cyclohexanone;

3-(2,4-dihydroxyphenyl)-2-cyclohexen-1-one oxime;

(+)-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(+)-4-[3-(1-piperazinyl)cyclohexyl]-1,3-benzenediol;

(±)-N-[3-(2,4-dihydroxyphenyl)cyclohexyl]methanesulfonamide;

(+)-4-[3-(hydroxymethyl)cyclohexyl]-1,3-benzenediol;

(+)4-[3-(hydroxyamino)cyclohexyl]-1,3-benzenediol;

cis/trans-4-[4-(hydroxymethyl)cyclohexyl]-1,3-benzenediol;

cis/trans-4-(4-hydroxy-4-methylcyclohexyl)-1,3-benzenediol;

(+)-O-methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(+)-3-(2,4-dihydroxyphenyl)-1-methylcyclohexanol;

.....

t · · · J (+)-O-benzyl-3-(2,4- ^dihydroxy -phenyl) ^{-cyclohexanone} - ^oxime ; '··' · ^: ·

3-(2,4-dihydroxyphenyl)-2-cyclopentanone oxime;

(±)-3-(2,4-dihydroxyphenyl)cyclopentanone;

(+)-3-(2,4-dihydroxyphenyl)cyclopentanone oxime;

4-(2,4-dihydroxyphenyl)-3-cyclohexen-1-one;

cis/trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetamide;

cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide;

trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]methanesulfonamide;

cis-N-[4-(1,4-dihydroxyphenyl)cyclohexyl]methanesulfonamide;

4-[4-(4-hydroxyphenyl)cyclohexyl]-1,3-benzenediol;

cis/trans-methyl-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

trans-methyl-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

cis-methyl-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

trans-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetic acid;

cis-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetic acid;

cis/trans-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetic acid;

cis/trans-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetonitrile;

cis/trans-4-[4-(2-aminoethyl)cyclohexyl]-1,3-benzenediol;

(±)-4-(3,3-difluoro ^{- cyclohexyl} ) ^-1,3 - ^benzoldiol ;

(±)-3-(2,4-dihydroxyphenyl)cyclohexanecarboxamide;

(±)-3-(2,4- ^dihydroxy -phenyl)-N- ^{hydroxycyclohexanecarboxamide} ;

(±)-3-(2,4- ^dihydroxy -phenyl) ^-N - ^{ethylcyclohexanecarboxamide} ;

(+)-4-[3- ^hydroxy -3-hydroxymethyl)cyclohexyl]-1,3-benzenediol;

(+)-N-[(2,4-dihydroxyphenyl)cyclohexyl]acetamide;

trans-4-(2,4-dihydroxyphenyl) ^cyclohexyl )-4-(dimethylamino)benzoate;

cis/trans-4-(2,4-dihydroxyphenyl)cyclohexanecarboxylic acid; ..........

trans-4-(2,4-dihydroxyphenyl)cyclohexylethylcarbamate;

trans-4-(2,4-dihydroxyphenyl)cyclohexylcyclohexylcarbamate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-4-tert-butylbenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-4-fluorobenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-4-trifluoromethylbenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-4-methoxybenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-4-methylbenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-4-chlorobenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-3,4-dimethylbenzoate;

trans-4-(2,4-dihydroxyphenyl)cyclohexyl-3,4-dichlorobenzoate;

trans-4-[4-(phenylsulfanyl)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(phenylsulfonyl)cyclohexyl]-1,3-benzenediol;

[4-(2,4-dihydroxyphenyl)cyclohexyl]methylpropionate;

ethyl 4-(2,4-dihydroxyphenyl)-1-hydroxycyclohexanecarboxylate;

cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol and their pharmaceutically acceptable salts.

The term "resorcinol derivatives" herein refers to a compound of general formula (I) consisting of a resorcinol ring singly substituted at the 4-position.

The term "alkyl group" means, unless otherwise indicated, a saturated, monovalent hydrocarbon group consisting of a straight, branched, cyclic carbon chain or a combination thereof, and may be optionally substituted. Any substituent or functional group may be located anywhere on the alkyl group where substitution is possible.

····. :

» * ······

The term "aryl group" herein means an optionally substituted phenyl group, the substitution being single or multiple, the number of substituents preferably being 0-2, independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino, di(C1-6) alkylamino, nitro, cyano or trifluoromethyl. Any substituent or functional group may be located anywhere on the aryl group, as indicated above.

The term "one or more substituents" herein refers to the number of substituents from one to the maximum number possible based on the available binding sites.

The term "halogen atom", unless otherwise indicated, means a chlorine, fluorine, bromine or iodine atom.

The term "acyl group", unless otherwise indicated, means a group of the general formula RCO, where R is an alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy group, wherein the terms "alkyl and aryl" are as defined above.

The term "acyloxy" herein refers to a group of the general formula O-acyl, wherein the term "acyl" is as defined above.

The term "C2-C9 heterocyclic cycloalkyl group" as used herein may mean pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1-3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. It is obvious to the skilled person that the said heterocyclic cycloalkyl groups having 2-9 carbon atoms can be linked via a carbon atom or via a nitrogen atom acting as a heteroatom, where possible.

1θ ·. .: : ···: ···:

The term "C2-C9 heteroaryl" as used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphtheny, isothianaphtheny, benzofuranyl, isobenzofuranyl, isoindolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, etc. It is obvious to the skilled person that the heteroaryl groups of 2-9 carbon atoms can be linked via a carbon atom or via the nitrogen atom acting as a heteroatom, where possible.

The compounds of formula (I) may contain chiral centers and thus exist in various enantiomeric and diastereomeric forms. The invention extends to the preparation of all optical isomers, stereoisomers, tautomers and mixtures thereof of the compounds of formula (I).

The general formula (I) defined above also describes compounds in which one or more hydrogen, carbon or other atoms are replaced by their isotope. These compounds can be used in pharmacokinetic studies of their metabolism and in binding studies as research and diagnostic tools.

The present invention also relates to the preparation of pharmaceutically acceptable acid addition and base addition salts of the compounds of formula (I). Acids which can be used to prepare pharmaceutically acceptable acid addition salts of the above-mentioned basic compounds of the invention include non-toxic anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,

.... _Λ . ........

tartrate, hydrogen tartrate, succinate, maleate, fumarate, gluconate/saccharal;· benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1-methylenebis(2-hydroxy-3-naphthoate) salts.

The present invention also provides various intermediates that can be used in the preparation of a wide variety of resorcinol derivatives.

The present invention provides an intermediate of general formula (4) wherein W, X and Y are as defined above.

In a preferred embodiment, the intermediate of formula (4) can be described by formula (4a) wherein W is as defined above and n is 0, 1, 2 or 3.

A further preferred intermediate of formula (4) is a compound of formula (4) or (4c) wherein W is as defined above.

Another preferred intermediate of formula (4) is the compound of formula (4d), wherein W and Z are as defined above, n is 0, 1, 2 or 3.

Another preferred intermediate of formula (4) is a compound of formula (4e) or (4f), wherein W and Z are as defined above.

Another preferred intermediate of formula (4) is the compound of formula (4g), wherein W and Z are as defined above and n is 0, 1, 2 or 3.

Further preferred intermediates of formula (4) are compounds of formula (4h) and (4i), wherein W and Z are as defined above.

The present invention further provides an intermediate of formula (5), wherein Q, W, X and Y are as defined above.

A preferred intermediate of formula (5) is the compound of formula (5a), wherein Q and W are as defined above and n is 0, 1, 2 or 3.

¹⁸ .... : ····—:

Another preferred intermediate of general formula (5) is the compound of formula (5bj'vag7^6)-arterane, where Q and W are as defined above.

Another preferred intermediate of formula (5) is the compound of formula (5d), wherein Q, W and Z are as defined above and n is 0, 1, 2 or 3.

A further preferred intermediate of formula (5) is a compound of formula (5e) or (5f), wherein Q, W and Z are as defined above.

Another preferred intermediate of formula (5) is the compound of formula (5g), wherein Q, W and Z are as defined above and n is 0, 1, 2 or 3.

Further preferred intermediates of formula (5) are compounds of formula (5h) and (5i), wherein Q, W and Z are as defined above.

A preferred intermediate of formula (5') is the compound of formula (5'a), wherein Q is as defined above and n is 0, 1, 2 or 3.

Further preferred intermediates of formula (5') are compounds of formula (5'b) and (5'c), wherein Q is as defined above.

Another preferred intermediate of general formula (5') is the compound of general formula (5'd) (5'e), where Q and Z are as defined above.

Another preferred intermediate of formula (5') is a compound of formula (5'f) or (5'g), wherein Q and Z are as defined above.

The production processes according to the present invention are shown in Figures 1 and 2.

Compound (2) of Figure 1 can be prepared from starting compound (1) which is commercially available (Aldrich Chemical Co.). The skilled person will of course be able to select the appropriate protecting group. A suitable protecting group is, for example, the benzyl group. The conversion to compound (2) is carried out under conventional conditions.

..............

For example, where the protecting group is a benzyl group, the water in the condensation of compound (1) and 0βηζίΐ8ίΚ0ϋόΙ·Κοζίΐ*Κοη is removed by a Dean-Stark apparatus. The condensation of compound (2) with compound (3) is carried out under conventional conditions, for example, by reacting compound (2) with a base, for example lithium diisopropylamide or lithium hexamethyldisilazide, in an ethereal medium, followed by the addition of compound (3) to give compound (4). Where W is hydrogen, the condensation of compound (2) with compound (3) requires at least two equivalents of a suitable base, for example lithium diisopropylamide, in a suitable medium, for example tetrahydrofuran containing a suitable cosolvent, such as hexamethylphosphoramide. Compound (4) can be reacted with a suitable halogenating agent, such as N-bromosuccinimide, in a chlorinated solvent, such as dichloromethane or chloroform, at room temperature to give compound (5), wherein Q is halogen, preferably bromine. Where W is hydrogen, compound (5) can exist in equilibrium with compound (5j). Alternatively, where W is hydrogen, compound (5') can be prepared directly by reacting compound (4) with a suitable halogenating agent. The process of the invention encompasses all of these different synthetic routes.

Compound (6) can be prepared from compound (5) or (5') under suitable conditions, such as reacting compound (5) or (5j) with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a suitable solvent, such as N,N-dimethylformamide at room temperature. Compound (la) can be prepared by conventional techniques, such as reacting compound (6) with triethylsilane in a chlorinated solvent in the presence of a Lewis acid, such as boron trifluoride, followed by removal of the protecting group under suitable conditions or hydrogenating compound (6) under conventional conditions. Compound (7) can be prepared from compound (5), (5') or (6) under conventional conditions. Compound (5), (5j) or (6) can be prepared in a suitable solvent, such as N,N-dimethylformamide at room temperature.

» T «····· in amide at a temperature of 140°C with a base, for example 1,5-diazabicyclo[1,2,3,4,5,6,7,8,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,2930,30,30,31,31,31,31,31,32,33,34,35,36,37,38,39,30,31,31,32,33,34,35,36,37,38,39,30,31,33,34,35,36,37,38,39,30,31,33,34,35,36,37,38,39,30,31,33,34,35,36,37,38,39,30,31,33,34,35,36,37,38,39,39,30,31,33,34,35,36,37,38,39,39,30,31,3

Compound (7) is hydrogenated under conventional conditions, for example in ethanol in the presence of a palladium/carbon catalyst under hydrogen gas, to give the compound of formula (Ia) when the protecting group is benzyl. Where W is a protecting group, the compound of formula (Ib) is obtained when compound (7) is treated under conventional reaction conditions which are apparent to those skilled in the art.

By conventional hydrogenation methods, such as those mentioned above, the compound of formula (Ib) can be converted to the compound of formula (Ia). The compound of formula (I) includes the compounds of formula (Ia) and (Ib).

Figure 2 shows a more specific process flow. Compound (8) can be prepared from commercially available starting material (1) (Aldrich Chemical Co.). The conversion to compound (8) is carried out under conventional conditions, for example, where the protecting group is benzyl, by condensing compound (1) with benzyl alcohol, removing water using a Dean-Stark apparatus. The condensation of compound (8) with compound (9) can be carried out by conventional techniques, for example, by reacting compound (8) with a base, such as lithium diisopropylamide, in an ethereal solvent, followed by the addition of compound (9) to give compound (10). Reaction of compound (10) with a suitable brominating agent, such as N-bromosuccinimide, in a chlorinated solvent at room temperature gives compound (11). Compound (11) can be converted to compound (12) under suitable reaction conditions by reacting compound (11) with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, in a suitable solvent, such as N,N-dimethylformamide, at 140°C. Compound (12) is subjected to hydrogenation under conventional conditions, such as ethanol/tetrahydrofuran in the presence of a palladium/carbon catalyst under hydrogen gas, to give the compound of formula (Ie) wherein the protecting group is a benzyl group. The compound of formula (Ie) is treated under acidic conditions to give the compound of formula (Id). The compound of formula (I) includes both compounds of formula (Ie) and formula (Id).

It will be apparent to those skilled in the art that the functional groups of the intermediates in the processes described above may require protection. The use of protecting groups is well known in the art and is fully described in, for example, the following works: "Protecting Groups in Organic Chemistry", ed.: McOmie, J. W. F., Plenum Press, 1973; "Protecting Groups in Organic Synthesis", 2nd ed., Greene, T. W. and Wurtz, P. G. M., Wiley-lnterscience, 1991 (incorporated herein by reference in their entirety).

The resorcinol derivatives prepared by the process described herein can be used for all the purposes previously described for compounds of this type. For example, resorcinol derivatives used as skin lightening agents or for other cosmetic purposes can be prepared by the process of the present invention.

Where the resorcinol derivatives of the present invention are used as skin lightening agents, these agents can be used to treat human pigmentation disorders including solar or simple freckles (including age-related liver spots), melasma/chloasma and post-inflammatory hyperpigmentation. These compounds reduce the level of melanin in the skin by inhibiting the production of melanin, either constitutively or as a result of UV radiation (e.g. exposure to sunlight). The compounds typically inhibit the enzyme tyrosinase. The active skin lightening compounds of the present invention can also be used to reduce the level of melanin in the skin in a non-pathological condition, i.e., when the user wishes to achieve a lightening of the skin color or to prevent the accumulation of melanin caused by UV light. The compounds can also be used with skin exfoliating agents (glycolic acid or trichloroacetic acid facial peels) to lighten the skin tone.

.... . . ........

• ^v ······ and to prevent re-pigmentation. The treatment regimen, the size of the doses used, the specific length of time between doses depend on the active ingredient used, the condition of the person being treated, and the nature and severity of the disorder or condition being treated. The active ingredient is used in a dose and frequency that will improve the disorder or condition being treated.

The active ingredient of the present invention can also be used with sunscreens (UVA or UVB blockers) to prevent repigmentation, protect the skin from tanning sunlight and ultraviolet light, or to enhance the melanin-lowering effect and skin lightening effect. The active ingredient of the present invention can be used in combination with retinoic acid or a derivative thereof or with any compound that acts on retinoic acid receptors and accelerates or enhances the reduction of melanin in the skin, the lightening processes or the accumulation of melanin desired by the invention. The active ingredient of the present invention can also be used in combination with 4-hydroxyanisole.

The active ingredient prepared according to the present invention can also be used in combination with ascorbic acid, an ascorbic acid derivative, an ascorbic acid-based product (e.g. magnesium ascorbate) or other antioxidants (e.g. resveratrol) that accelerate or enhance the skin's ability to reduce melanin levels and lighten skin.

The skin lightening agents prepared according to the invention are generally used in the form of pharmaceutical compositions which contain at least one compound of the general formula (I) together with a pharmaceutically acceptable carrier or vehicle. These compositions are prepared with conventional solid or liquid carriers or vehicles suitable for topical application in the form of solutions, gels, creams, jellies, pastes, rinses, ointments, salves, sprays, etc.

Such a carrier may be, for example, an aqueous or aqueous/alcoholic ‘oil-in-water’ or ‘water-in-oil’ type emulsion, an emulsified gel or a two-phase system. The compositions according to the invention are preferably in the form of a rinse, cream, milk, gel, pack, microsphere or nanosphere or vesicular dispersion.

The skin lightening compositions generally contain the resorcinol derivative prepared according to the invention in an amount of 0.01-10%, preferably 0.1-10%, based on the total weight of the composition.

The efficacy of the skin lightening resorcinol derivatives prepared according to the present invention can be determined in conventional manner by their ability to inhibit the enzyme tyrosinase or by the assay methods described below.

(1) Tyrosinase (DOPA oxidase) assay using cell lysate:

In cell lysate assays and screening assays, human melanoma cell line SKMEL 188 (Memorial Sloan-Kettering) is used. The test compound and L-dihydroxyphenylalanine (L-DOPA, 100 pg/ml) are incubated with cell lysate containing human tyrosinase for 8 hours, and the plates are then read at 405 nm. The potency of the test compounds in the DOPA oxidase assays correlates very well with the results obtained in the tyrosine hydroxylase assays using ³ H-tyrosine as the substrate.

(2) Melanin assay using human primary melanocytes:

The test compound is incubated with human primary melanocytes in the presence of α-melanocyte stimulating hormone (α-MSH) for 2-3 days. The cells are then lysed with sodium hydroxide and sodium dodecyl sulfate (SDS) and melanin values are read at 405 nm. Alternatively, ¹⁴ C-DOPA is added to the cells in combination with tyrosinase inhibitors and the amount of acid-insoluble ¹⁴ C-melanin is determined by scintillation counting. The IC ₅₀ value indicates the inhibitory effect of the compound on α ^- MSH-stimulated melanin synthesis.

(3) Tyrosine kinase assay (TK):

Purified c-met, erb-B2 or IGF-r tyrosine kinase domains can be used for TK assays. Specific antibodies against the phosphorylated tyrosine residue are used in the assays. The color reaction is performed with horseradish peroxidase bound to the antibody.

(4) Human skin model:

Human melanocytes and keratinocytes are grown at the air/liquid interface. This tissue culture forms a three-dimensional structure that histologically and microscopically resembles the epidermis of human skin. Test compound is applied to the top of the cells to mimic the topical application of the drug. After three days of incubation (10 μM test compound), the cells are washed thoroughly and lysed for the DOPA oxidase assay.

(5) Interleukin-1 (L-1) assay:

IL-1 ELISA assay system (R & D system) was used to investigate the effect of the compound on IL-1 secretion in human skin model. IL-1 is a pro-inflammatory cytokine that plays a role in UV-induced skin inflammation.

(6) In vivo test:

For the tests, black or brown guinea pigs with homogeneous skin color are used. The animals are treated twice daily for 4-8 weeks, five times a week, with a solution of the compound of general formula (I) (5% solution in a mixture of ethanol/propylene glycol in a ratio of 70:30) and vehicle (control). Depigmentation can be determined by subtracting the light reflectance of the treated skin from the light reflectance of the untreated skin.

To illustrate the above, the following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. The proton magnetic resonance spectrum (400 MHz, ¹ H-NMR) is recorded with solutions prepared in DMSO-de, CDCl3 or d ₄ -MeOH, and the positions of the peaks are given in parts per million (ppm) measured down from the tetramethylsilane peak. The abbreviations for the shape of the peaks are: s - singlet, d - doublet, t - triplet, q - quartet, m - multiplet, sz - broad.

Example 1

Preparation of the intermediate 3-(benzyloxy)-2-cyclohexen-1-one

Into a round-bottom flask equipped with a magnetic stirrer and a Dean-Stark apparatus were weighed 70.0 g (624 mmol) of 1,3-cyclohexanedione, 500 ml of toluene, 1.68 g (8.83 mmol) of p-toluenesulfonic acid monohydrate and 65.6 g (606 mmol) of benzyl alcohol. The resulting solution was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and washed with 4x50 ml of saturated aqueous sodium bicarbonate solution. The organic phase was washed with 50 ml of brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a brown oil which crystallized on standing. The crude crystalline material was pre-slurried in 100 ml of isopropyl ether and stirred at 0°C for 2 hours. The mixture was filtered, the crystalline material was washed with 3x100 ml of ice-cold isopropyl ether, then with 100 ml of petroleum ether. The resulting solid was dried under reduced pressure overnight to give 85.3 g (68%) of the title compound. TS: (m/z), (ES ⁺ ) 203 (M+H ⁺ ).

Example 2

Preparation of the intermediate (±)3-(benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4,5]dec-8-yl)-2-cyclohexen-1-one

Into a round-bottomed flask equipped with a magnetic stirrer, '·6'0θ ^: · nit* anhydrous tetrahydrofuran and 38.1 ml (272 mmol) diisopropylamine are weighed. The stirred solution is cooled to -78°C and 113.4 ml of a 2.4 mol/liter solution of n-butyllithium in hexane (272 mmol) is added in 20 ml portions via a syringe. The resulting yellow solution is stirred at -78°C for 35 minutes, then a solution of 50.0 g (248 mmol) of 3-(benzyloxy)-2-cyclohexen-1-one in 100 ml of anhydrous tetrahydrofuran is added. The solution was stirred for one hour, then a solution of 37.7 g (248 mmol) of cyclohexane-1,4-dione monoethyl ketal in 100 ml of anhydrous tetrahydrofuran was added to the solution. The solution was stirred at -78°C for 2 hours, then allowed to slowly warm to room temperature over 1 hour. 80 ml of saturated aqueous ammonium chloride solution, then 700 ml of dichloromethane were added to the reaction mixture and stirred until no undissolved solid remained. The phases were separated, and the aqueous phase was extracted with 2x100 ml of dichloromethane. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting solid was triturated with methanol to give 78.4 g (88%) of the title compound. TS: (m/z), (ES ⁺ ) 359 (M+H ⁺ ).

Example 3

Preparation of the intermediate (±)-1-(benzyloxy)-6-bromo-3-(1,4-dioxaspiro4,5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one

In a round-bottomed flask equipped with a magnetic stirrer, 78.4 g (219 mmol) of (+)-3-(benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4,5]dec-8-yl)-2-cyclohexen-1-one and 600 ml of dichloromethane are weighed. To the stirred solution, 40.9 g (230 mmol) of N-bromosuccinimide are added in one portion, followed by 3 drops of 48% aqueous hydrobromic acid. The resulting solution is stirred at room temperature for 2 hours, then poured into a separatory funnel containing 150 ml of saturated aqueous sodium metabisulfite solution and 200 ml of dichloromethane and shaken thoroughly. The phases were separated, the organic phase was dried over 200 ml of brine ^: ^sti· Ymagnesium sulfate and evaporated under reduced pressure. The resulting solid was triturated in 500 ml of methanol to give 82.8 g (86%) of the title compound as a white solid. TS: (m/z), (ES ⁺ ) 437 and 439 (M+H ⁺ ) [(1:1), M+H ⁺ ], Example 4

Preparation of the intermediate 5-(ϋθηζιΊ-χϊ)-2-(1,4-άΐχ35ρίΓθΓ4.51άβο-7-έη-8-ίΙ)ΤβηοΙ

A round-bottomed flask was charged with 36.0 g (82.4 mmol) of (+)-1-(benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4,5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one and 300 ml of anhydrous N,N-dimethylformamide. To the stirred solution was added 13.6 ml (90.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in one portion, and the mixture was stirred at 140°C with vigorous stirring for 19 hours. The reaction mixture was allowed to cool to room temperature and most of the solvent was removed under reduced pressure. The resulting oily residue was partitioned between 500 ml of dichloromethane and 100 ml of water, the phases were separated, the organic phase was washed with 2x100 ml of water and then with 100 ml of brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a brown solid which was adsorbed onto silica gel. The product was purified by flash chromatography (eluent dichloromethane, then ethyl acetate/petroleum ether 1:1) to give an off-white solid which was triturated in 50 ml of methanol. The slurry was stirred for 20 min, filtered and the filtrate was washed with 50 ml of methanol. After removal of the solvent under reduced pressure, 18.2 g (65%) of the title compound was obtained as a white solid. TS: (m/z) (ES ⁺ ) 339 (M+H ⁺ ).

Example 5

Preparation of 4-(1,4-dioxaspiror4.5ldec-8-yl)-1,3-benzenediol

Into a round-bottomed flask equipped with a magnetic stirrer, 14.5% (2.8%) of 5-(benzyloxy)-2-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)phenol and 50 ml of tetrahydrofuran were weighed. The stirred mixture was heated gently until all solids dissolved, and the solution was allowed to cool to room temperature. 100 ml of ethanol and 4.54 g of palladium/carbon catalyst (10% palladium on activated carbon) were added to the flask. The air was evacuated from the reaction vessel and replaced with hydrogen gas and stirred vigorously for 24 hours. The reaction mixture was filtered through a celite pad, and the filter pad was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give an off-white solid. The crude product was slurried in 200 mL of dichloromethane and filtered through a fritted glass filter to give 10.2 g (95%) of the title compound as a white solid. TS: (m/z) (ES ⁺ ) 251 (M+H ⁺ ).

Example 6

Preparation of 4-(2,4-dihydroxyphenyl)cyclohexanone

In a round-bottomed flask equipped with a magnetic stirrer, 11.3 g (45.2 mmol) of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1,3-benzenediol, 250 mL of acetone and 50 mL of water were weighed. To the stirred solution, 1.14 g (4.52 mmol) of pyridinium p-toluene sulfate was added in one portion and the reaction mixture was refluxed for 8 hours. After allowing the reaction mixture to cool to room temperature, most of the acetone was removed under reduced pressure and the residue was partitioned between 200 mL of ethyl acetate and 50 mL of water. The aqueous phase was extracted with ethyl acetate (3x50 ml), the combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an off-white powder. The powder was washed with dichloromethane (100 ml) and the solvent was removed under reduced pressure to give 9.30 g (100%) of the title compound as an off-white powder. TS: (m/z) (ES ⁺ ) 207 (M+H ⁺ ).

¹ H-NMR (CD ₃ OD), δ: 1.84-1.97 (2H, m), 2.15-2.23 (2H, m), 2.36-2.4¾' (Th, m)? 2.582.68 (2H, m), 3.39 (1H, tt), 6.26 (1H, dd), 6.34 (1H, d), 6.96 (1H, d).

The patents, patent applications, and communications mentioned herein are incorporated herein by reference.

The scope of the invention is not limited to the embodiments described herein, which are merely illustrative of certain aspects of the present invention, and functionally identical methods and components are included within the scope of the invention. It will be apparent to those skilled in the art that various modifications of the methods described and illustrated herein may be made, which are also included within the scope of the invention.

Claims (52)

PATENT CLAIMS ^T '-' *” '“'** 1. Procedure according to the general formula (6) - where W represents a hydrogen atom or a protecting group; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NHgeneral formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino- ⁽ C1-6)-acyl group, -CO ₂ R , -(C1-6 'alkyl'-CO ₂ R ² , C(O)N(R ² )2, -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C 1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C 1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, wherein R ² independently represents a hydrogen atom, a C 16 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ group of the general formula C(O)O-, where R ³ represents a C 1-6 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O)2-, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-C6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-C6)-alkyl, -NH-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl-HN- or ketal groups, which comprises reacting the compound of formula (5) or (5') - where Q is a halogen atom, W, X and Y are as defined above - with a base to obtain the compound of formula (6). 2. The process of claim 1, wherein Q is bromine, iodine or chlorine. 3. The process of claim 1, wherein Q is bromine. 4. Procedure with general formula (7) - where W represents a hydrogen atom or a protecting group; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6 alkyl)-CO ₂ R ² , C(O)N(R ² )2, -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, in which R ² independently represents a hydrogen atom, a C16 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O- group of the general formula, in which R ³ represents a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O)2-, R ⁴ R ⁵ NS(O)2-(C 1-6 )-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C 1-6 )-serthrophyllo)-alkyl groups of the general formula, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C 1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-C6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-C6)-alkyl, -NH-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl-HN- or ketal groups, for the preparation of a compound, which comprises reacting the compound of formula (5) or (5') - where Q is a halogen atom, W, X and Y are as defined above - with a base to obtain the compound of formula (7). 5. The process of claim 4, wherein Q is bromine, iodine or chlorine. 6. The process of claim 4, wherein Q is bromine. 7. The process according to claim 1 or 4, wherein the compound of general formula (5) is prepared by reacting the compound of general formula (4) - wherein W, X and Y are as defined above - with a halogenating agent. 8. The process of claim 7, wherein the halogenating agent is a brominating agent. 9. The process of claim 8, wherein the brominating agent is N-bromosuccinimide. 10. The process according to claim 7, wherein the compound of formula (4) is prepared by reacting the compound of formula (2) with the compound of formula (3) in the presence of a base, wherein W, X and Y are as defined above. 11. Procedure according to the general formula (5) - where Q represents a halogen atom; W represents a protecting group; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH, (C1-6)-alkylamino-CO-, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl- (C1-6)-alkyl-, C1-6-alkoxy-(C1-6)-acyl-amino-, C1-6-amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6-alkyl-amino-(C1-6)-acyl-, (C1-6-alkyl) ₂ -amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6-alkyl)-CO ₂ R ² , C(O)N(R ² )2, -(C1-6-alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6-alkyl)-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O) _m R ² general ³⁵ ·: : “? groups of the formula, wherein R ² independently represents a hydrogen atom, a C 1-6 alkyl, aryl or aryl-(C 1-6 )-alkyl group; R ³ represents a group of the general formula C(O)O-, wherein R ³ represents a C 1-6 alkyl, aryl or aryl-(C 1-6 )-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- or ketal groups, which comprises reacting the compound of formula (4) - where W, X and Y are as defined above - with a halogenating agent to obtain the compound of formula (5). 12. The process of claim 11, wherein the halogenating agent is a brominating agent. 13. The process of claim 12, wherein the brominating agent is N-bromosuccinimide. 14. The process according to claim 11, wherein the compound of formula (4) is prepared by reacting the compound of formula (2) with the compound of formula (3) in the presence of a base, wherein W, X and Y are as defined above. 15. Process of general formula (5’) - where Q represents a halogen atom; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6 alkyl)-CO2R ² , C(O)N(R ² )2i -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6 )-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, within which R ² independently represents a hydrogen atom, a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O- group of the general formula, where R ³ represents a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent hydrogen or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ) groups, where R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-6)-alkyl, -NH-(C1-6)-alkyl, aryl-(C1-6)-alkyl-HN- groups or ketal group compound, which consists in reacting the compound of general formula (4) - where W represents a hydrogen atom, X and Y are as defined above - with a halogenating agent, to obtain the compound of general formula (5 j. 16. The process of claim 15, wherein the halogenating agent is a brominating agent. 17. The process of claim 16, wherein the brominating agent is N-bromosuccinimide. 18. The process according to claim 15, wherein the compound of formula (4) is prepared by reacting the compound of formula (2) with the compound of formula (3) in the presence of a base, wherein W, X and Y are as defined above. 19. Procedure with general formula (4) - where W represents a hydrogen atom or a protecting group; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6 alkyl)-CO2R ² , C(O)N(R ² )2i -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ^Z (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, wherein R ² independently represents a hydrogen atom, a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ group of the general formula C(O)O-, where R ³ represents a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O) _2R ⁵ N-(C1-6)-alkyl groups of the general formula, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ )2), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- groups or ketal groups for the preparation of a compound, which consists in reacting the compound of general formula (2) with the compound of general formula (3) - where X and Y are as defined above - in the presence of a base, to obtain the compound of general formula (4). 20. Process of general formula (la) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano -(C1-6)-alkyl-, halogenated C1-6-alkyl-, C1-6* ·η«Γθ-alkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, C1-6-acyl-amino-, C1-6-acyl-amino-(C1-6)-alkyl-, C1-6-alkoxy-(C1-6)-acyl-amino-, C1-6-amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6-alkyl-amino-(C1-6)-acyl-, (C1-6-alkyl) ₂ -amino-(C1-6)-acyl-group, -CO ₂ R ² , -(C1-6-alkyl)-CO ₂ R ² , C(O)N(R ² )2, -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O) _m R ² groups of the general formula, within which R ² independently represents a hydrogen atom, a C1-C6 alkyl, aryl or aryl-(C1-6)-alkyl group; a group of the general formula RC(O)O-, where R ³ is a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- or ketal groups, which comprises (a) reacting the compound of formula (5) or (5') - where Q is a halogen atom, W is a hydrogen atom or a protecting group, X and Y are as defined above - with a base to obtain the compound of formula (6); and (b) where W is a hydrogen atom, the compound of formula (6) thus obtained is reducing the compound to obtain the compound of general formula (Ia); or (c) where W represents a protecting group, reducing the thus obtained compound of general formula (6) and removing the protecting group to obtain the compound of general formula (Ia). 21. Process of general formula (la) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6 )-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6 )-acyl-(C1-6 )-alkyl-, C1-6 alkyl-amino-(C1-6 )-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6 )-acyl group, -CO ₂ R ² , -(C1-6 alkyl)42 ·; ; ........ -CO ₂ R ² , C(O)N(R ² )2i -(C 1-6 alkyl)-C(O)N(R ² )2, R ² ON^f R*O^ (ΐ-6'-phenyl)-alkyl-, R ² ON=CR ² -(C 1-6)-alkyl-, NR ² (OR ² ), -(C 1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C 1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, within which R ² independently represents a hydrogen atom, a C 1-6 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ C(O)O- is a group of the general formula, where R ³ is an alkyl, aryl or aryl-(C1-6)-alkyl group having 1-6 carbon atoms; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O)2R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O) ₂ R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ )2), wherein R ⁶ is OR ² or R ² , wherein R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- or ketal groups, which comprises (a) reacting the compound of formula (5) or (5') - wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, X and Y are as defined above - with a base to obtain the compound of formula (7); and (b) where W is a hydrogen atom, the compound of formula (7) thus obtained is reducing the compound to obtain the compound of formula (Ia); or (c) where W is a protecting group, reducing the compound of formula (7) thus obtained and removing the protecting group to obtain the compound of formula (Ia). 22. Process of general formula (la) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6 alkyl)-CO ₂ R ² , C(O)N(R ² )2, -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C 1-6 alkyl)-C(O)(NR ² OR ² ), -S(O) _m R ² groups of the general formula, wherein R ² independently represents a hydrogen atom, a C 1-6 alkyl, aryl or aryl-(C 1-6) alkyl group; R ³ group of the general formula C(O)O-, where R ³ represents a C 1-6 alkyl, aryl or aryl-(C 1-6) alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-*'r' ⁴ R'NS^0) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O) ₂ R ⁵ N-(C1-6)-alkyl groups of the general formula, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ )2), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- or ketal groups, which comprises (a) reacting the compound of formula (5) or (5') - wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above - with a base to obtain the compound of formula (6); (b) reacting the thus obtained compound of formula (6) with a base to obtain the compound of formula (7); and (c) where W represents a hydrogen atom, hydrogenating the thus obtained compound of formula (7) to obtain the compound of formula (Ia); or (d) where W represents a protecting group, hydrogenating the thus obtained compound of formula (7) and removing the protecting group to obtain the compound of formula (Ia). 23. Process of general formula (la) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, ^C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)alkyl, oxo, =CHO-(C1-6)alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(1-6C)-alkylamino-, 1-6C-aminoalkyl-, 1-6C-alkoxy-CO-NHgeneral formula, 1-6C-alkylamino-CO-general formula, 2-6C-alkenyl-, 2-6C-alkynyl-, 1-6C-hydroxyalkyl-, 1-6C-alkoxy(1-6C)-alkyl-, 1-6C-acyloxy-(1-6C)-alkyl-, nitro-, cyano-(1-6C)-alkyl-, halogenated 1-6C-alkyl-, 1-6C-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(1-6C)-alkyl-, 1-6C-acylamino-, 1-6C-acylamino-(1-6C)-alkyl- (C1-6)-alkyl, (C1-6)-alkoxy-(C1-6)-acyl-amino, (C1-6)-amino-acyl, (C1-6)-acyl-(C1-6)-alkyl, (C1-6)-alkylamino-(C1-6)-acyl, (C1-6)-alkyl)2-amino-(C1-6)-acyl, -CO2R ² , -(C1-6)-alkyl-CO2R ² , C(O)N(R ² )2, -(C1-6)-alkyl-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), ^- (C1-6 alkyl) ^-NR2 ( ^OR2 ), -C(O)( ^NR2OR2 ), -(C1-6 alkyl)-C(O) ^{( NR2OR2} ), -S(O) ^mR2 , wherein ^R2 is independently hydrogen, C1-6 alkyl, aryl or aryl(C1-6) alkyl; ^{R3 is} a C(O)O- group, wherein ^R3 is C1-6 alkyl, aryl or aryl(C1-6) alkyl; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O)2-, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O) ₂ R ⁵ N-(C1-6)-alkyl, where m is 0, 1 or 2 and R ⁴ and R ⁵ are 46 ··': .: ; each independently represents a hydrogen atom or a C1-C6 alkyl group; groups of the general formula -C(=NR ⁶ )(N(R ⁴ )2), -(C1-C6 alkyl)-C(=NR ⁶ (N(R ⁴ )2), wherein R ⁶ represents OR ² or R ² , where R ² is as defined above; groups of the general formula -OC(O)-aryl-(C1-C6)-alkyl, -NH-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl-HN- or ketal group (a) the compound of the general formula (5) or 5') - where Q represents a halogen atom, W represents a hydrogen atom or a protecting group, X and Y are as defined above - is reacted with a base, to obtain the compound of the general formula (6); (b) reacting the thus obtained compound of formula (6) with a base to obtain the compound of formula (7); and (c) where W represents a hydrogen atom, hydrogenating the thus obtained compound of formula (7) to obtain the compound of formula (Ia); or (d) where W represents a protecting group, removing the protecting group from the thus obtained compound of formula (7) and hydrogenating the thus obtained compound of formula (Ib) to obtain the compound of formula (Ia). 24. Process of general formula (la) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, where Z independently represents 47 .............. • · · · · · cyano-, halogen-, C1-6 alkyl-, aryl-, C2-9 heteroalkyl-, C2-9 heteroaryl-, aryl-(C1-6)-alkyl-, oxo-, =CHO-(C1-6)-alkyl-, amino-, hydroxyl-, C1-6 alkoxy-, aryl-(C1-6)-alkoxy-, C1-6 acyl-, C1-6 alkylamino-, aryl-(C1-6)-alkylamino-, C1-6 aminoalkyl-, C1-6 alkoxy-CO-NH-, C1-6 alkylamino-CO-, C2-6 alkenyl-, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 alkoxy(C1-6)alkyl, C1-6 acyloxy-(C1-6)alkyl, nitro, cyano-(C1-6)alkyl, halogenated C1-6 alkyl, C1-6 nitroalkyl, trifluoromethyl, trifluoromethyl-(C1-6)alkyl, C1-6 acylamino, C1-6 acylamino-(C1-6)alkyl, C1-6 alkoxy-(C1-6)acylamino, C1-6 aminoacyl, amino-(C1-6)acyl-(C1-6)alkyl, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl group, -CO ₂ R ² , -(C1-6 alkyl)-CO2R ² , C(O)N(R ² )2i -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, within which R ² is independently hydrogen, alkyl, aryl or aryl-(1-6C)-alkyl; R ³ C(O)O-, where R ³ is alkyl, aryl or aryl-(1-6C)-alkyl; R ³ C(O)O-(1-6C)-alkyl, R 4 R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O) ^2- (1-6C)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(1-6C)-alkyl, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent hydrogen or alkyl; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-C6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-C6)-alkyl, -NH-(C1-C5)-alkyl, aryl-(C1-C6)-alkyl-HN- or ketal groups, which comprises (a) reacting the compound of formula (5) or (5') - wherein Q is a halogen atom, W is a hydrogen atom or a protecting group, and X and Y are as defined above - with a base to obtain the compound of formula (7); (b) where W is a hydrogen atom, the compound of formula (7) thus obtained is hydrogenated to give the compound of formula (Ia); or (c) where W is a protecting group, the compound of formula (7) thus obtained is deprotected and the compound of formula (Ib) thus obtained is hydrogenated to give the compound of formula (Ia). 25. Process of general formula (Ib) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-, (C1-6)-alkylamino-CO-, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl- (C1-6)-alkyl-, C1-6-alkoxy-(C1-6)-acyl-amino-, C1-6-amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6-alkyl-amino-(C1-6)-acyl-, (C1-6-alkyl) ₂ -amino-(C1-6)-acyl-, -CO2R ² , -(C1-6-alkyl)-CO2R ² , C(O)N(R ² )2, -(C1-6-alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, wherein R ² independently represents a hydrogen atom, a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ group of the general formula C(O)O-, where R ³ represents a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O)2-, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-C6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-C6)-alkyl, -NH-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl-HN- or ketal groups, for the preparation of a compound, which comprises (a) reacting the compound of formula (5) or (5') - where Q is a halogen radical; W*] is a hydrogen atom or a protecting group, X and Y are as defined above - with a base to obtain the compound of formula (6); (b) reacting the compound of formula (6) thus obtained with a base to obtain the compound of formula (Ib) when W is a hydrogen atom or the compound of formula (7) when W is a protecting group; and (c) when W is a protecting group, removing the protecting group from the compound of formula (7) thus obtained to obtain the compound of formula (Ib). 26. Process of general formula (Ib) - where X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano -(C1-6)-alkyl-, halogenated C1-6-alkyl-, 1-hexadecyl * nitro-alkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, C1-6-acyl-amino-, C1-6-acyl-amino-(C1-6)-alkyl-, C1-6-alkoxy-(C1-6)-acyl-amino-, C1-6-amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6-alkyl-amino-(C1-6)-acyl-, (C1-6-alkyl) ₂ -amino-(C1-6)-acyl-group, -CO ₂ R ² , -(C1-6-alkyl)-CO ₂ R ² , C(O)N(R ² )2, -(C 1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C 1-6)-alkyl-, R ² ON=CR ² -(C 1-6)-alkyl-, NR ² (OR ² ), -(C 1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C 1-6 alkyl)-C(O)(NR ² OR ² ), -S(O) _m R ² groups of the general formula, within which R ² independently represents a hydrogen atom, a C 1-6 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ C(O)O- group, where R ³ is a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O) ₂ R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C 1-6 alkyl)-C(=NR ⁶ (N(R ⁴ )2), wherein R ⁶ is OR ² or R ² , wherein R ² is as defined above; -OC(O)-aryl-(C 1-6)-alkyl, -NH-(C 1-6)-alkyl, aryl-(C 1-6)-alkyl-HN- or ketal groups, which comprises (a) reacting a compound of formula (5) or (5') - wherein Q is halogen, W is hydrogen or a protecting group, X and Y are as defined above - with a base to obtain a compound of formula (Ib) - when W is hydrogen - or of formula (7) - when W is a protecting group; and ⁵² : ^: ·· - : ^: * (b) when W represents a protecting group, the protecting group is removed from the thus obtained general compound (7) to obtain the compound of general formula (Ib). 27. The process of claim 1, wherein X and Y, together with the carbon atom to which they are attached, form a C4-8 cycloalkyl or C5-8 cycloalkenyl group, which groups are optionally substituted. 28. The process of claim 27, wherein the C4-8 cycloalkyl or C5-8 cycloalkenyl group is substituted with 1-3 independently selected Z substituents. 29. The process of claim 27, wherein X and Y together with the carbon atom to which they are attached form a cyclohexyl or cyclohexenyl group. 30. The process of claim 27, wherein X and Y together with the carbon atom to which they are attached form a cyclopentyl or cyclopentenyl group. 31. The process of claim 27, wherein the C4-8 cycloalkyl or C5-8 cycloalkenyl group is unsubstituted. 32. The process of claim 27, wherein the C4-8 cycloalkyl or C5-8 cycloalkenyl group is monosubstituted. 33. The process of claim 27, wherein the C4-8 cycloalkyl or C58 cycloalkenyl group is disubstituted. 34. The process of claim 29, wherein the cyclohexyl or cyclohexenyl group is monosubstituted at the 3- or 4-position. 35. The process of claim 30, wherein the cyclopentyl or cyclopentenyl group is monosubstituted at the 3-position. 36. A compound of general formula (4), wherein W represents a hydrogen atom or a protecting group; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl)2-amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6 alkyl)-CO2R ² , C(O)N(R ² )2i -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of general formula ⁵⁴ ·: : /, within which R ² independently represents* hydrogen*gerium atom, C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ group of general formula C(O)O-, where R ³ represents C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-6)-alkyl, -NH-(C1-6)-alkyl, aryl-(C1-6)-alkyl-HN- or ketal. 37. A compound of formula (4a) according to claim 36, wherein W is as defined above, n is 0, 1, 2 or 3. 38. A compound of formula (4b) or (4c) according to claim 37, wherein W is as defined above. 39. A compound of formula (4d) according to claim 36, wherein W and Z are as defined above, n is 0, 1, 2 or 3. 40. A compound of formula (4e) or (4f) according to claim 39, wherein W and Z are as defined above. 41. A compound of formula (4g) according to claim 36, wherein W and Z are as defined above, n is 0, 1, 2 or 3. 42. A compound of formula (4h) or (4i) according to claim 41, wherein W and Z are as defined above. 43. A compound of formula (5) wherein Q is a halogen atom; W represents a hydrogen atom or a protecting group; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl-, -CO ₂ R ² , -(C1-6 alkyl)-CO ₂ R ² , C(O)N(R ² )2, -(C1-6 alkyl)-C(O)N(R ² )2, R ² ON=, R ² ON=(C1-6)-alkyl-, R ² ON=CR ² -(C1-6)-alkyl-, NR ² (OR ² ), -(C1-6 alkyl)56 ..-j _t . j ; -NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C 1-6 alkyl)-C(O)(NR ² OR ² ),'-SfOjmR^groups of the general formula, within which R ² independently represents a hydrogen atom, a C 1-6 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ group of the general formula C(O)O-, where R ³ represents a C 1-6 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-6)-alkyl, -NH-(C1-6)-alkyl, aryl-(C1-6)-alkyl-HN- or ketal. 44. A compound of formula (5a) according to claim 43, wherein Q and W are as defined above, n is 0, 1, 2 or 3. 45. A compound of formula (5b) or (5c) according to claim 44, wherein Q and W are as defined above. 46. A compound of formula (5d) according to claim 43, wherein Q, W and Z are as defined above, n is 0, 1, 2 or 3. 47. A compound of formula (5e) or (5f) according to claim 46, wherein Q, W and Z are as defined above. 48. A compound of formula (5g) according to claim 43, wherein Q, W and Z are as defined above and n is 0, 1, 2 or 3. 49. A compound of formula (5H) or (5i) according to claim 48, wherein Q, W and Z are as defined above. 50. The compound of claim 43, wherein Q is bromine, iodine or chlorine. 51. The compound of claim 43, wherein Q is brominated. 52. A compound of general formula (5’), where Q represents a halogen atom; X and Y are independently hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or X and Y together with the carbon atom to which they are attached form a C4-C8 cycloalkyl or C5-C8 cycloalkenyl group, provided that the C4-C8 cycloalkyl and C5-C8 cycloalkenyl rings are non-aromatic; and wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C4-8 cycloalkyl and C5-8 cycloalkenyl groups are optionally substituted with 1-3 Z substituents, wherein Z is independently selected from cyano, halogen, C1-6 alkyl, aryl, C2-9 heterocyclic cycloalkyl, C2-9 heteroaryl, aryl-(C1-6)-alkyl, oxo, =CHO-(C1-6)-alkyl, amino, hydroxyl, C1-6 alkoxy, aryl-(C1-6)-alkoxy, C1-6 acyl, C1-6 alkylamino, aryl-(C1-6 (C1-6)-alkylamino-, (C1-6)-aminoalkyl-, (C1-6)-alkoxy-CO-NH-general formula, (C1-6)-alkylamino-CO-general formula, (C2-6)-alkenyl-, (C2-6)-alkynyl-, (C1-6)-hydroxyalkyl-, (C1-6)-alkoxy(C1-6)-alkyl-, (C1-6)-acyloxy-(C1-6)-alkyl-, nitro-, cyano-(C1-6)-alkyl-, halogenated (C1-6)-alkyl-, (C1-6)-nitroalkyl-, trifluoromethyl-, trifluoromethyl-(C1-6)-alkyl-, (C1-6)-acylamino-, (C1-6)-acylamino-(C1-6)-alkyl-, C1-6 alkoxy-(C1-6)-acyl-amino-, C1-6 amino-acyl-, amino-(C1-6)-acyl-(C1-6)-alkyl-, C1-6 alkyl-amino-(C1-6)-acyl-, (C1-6 alkyl) ₂ -amino-(C1-6)-acyl group, -CO ₂ R ² , -(C1-6 alkyl)58 • ' -”*·-** -CO ₂ R ² , C(O)N(R ² )2, -(C 1-6 alkyl)-C(O)N(R ² )2, R ² ON-, ' R ² oXf=(TJfe'%sene)-alkyl-, R ² ON=CR ² -(C 1-6)-alkyl-, NR ² (OR ² ), -(C 1-6 alkyl)-NR ² (OR ² ), -C(O)(NR ² OR ² ), -(C 1-6 alkyl)-C(O)(NR ² OR ² ), -S(O)mR ² groups of the general formula, within which R ² independently represents a hydrogen atom, a C 1-6 alkyl, aryl or aryl-(C 1-6)-alkyl group; R ³ C(O)O- group, where R ³ is a C1-6 alkyl, aryl or aryl-(C1-6)-alkyl group; R ³ C(O)O-(C1-6)-alkyl, R ⁴ R ⁵ NC(O)-O-, R ⁴ R ⁵ NS(O) ₂ -, R ⁴ R ⁵ NS(O)2-(C1-6)-alkyl, R ⁴ S(O)2R ⁵ N-, R ⁴ S(O)2R ⁵ N-(C1-6)-alkyl groups, where m is 0, 1 or 2 and R ⁴ and R ⁵ independently represent a hydrogen atom or a C1-6 alkyl group; -C(=NR ⁶ )(N(R ⁴ )2), -(C1-6 alkyl)-C(=NR ⁶ (N(R ⁴ ) ₂ ), wherein R ⁶ is OR ² or R ² , where R ² is as defined above; -OC(O)-aryl-(C1-6)-alkyl, -NH-(C1-6)-alkyl, aryl-(C1-6)-alkyl-HN- or ketal. The authorized person: Áda Szentpéteri Jr. fencer H-fífcZ B Phone?3^-24-95t Otter