Aminophosphinic derivatives for preventing and treating eye pain

Abstract

The disclosure relates to formula (I) compounds R1-NH—CH(R2)-P(=0)(OH)—CH2-C(R3)(R4)-CONH—C(R5)(R6)-COOR7 for the use thereof in treating and/or preventing eye pain.

1 . A compound having the formula (I):
   R 1 —NH—CH(R 2 )—P(═O)(OH)—CH 2 —C(R 3 )(R 4 )—CONH—C(R 5 )(R 6 )—COOR 7   (I)
   
       wherein:
 R 1  is:
 a hydrogen 
 an (acyloxy)alkyl carbamate group —C(═O)—O—C(R)(R′)—OC(═O)—R″ wherein R and R′ are each independently a hydrogen, an alkyl group and R″ is an alkyl group; 
 
 R 2  is:
 a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 carbon atoms; 
 
 R 3  and R 4  are each independently:
 a hydrogen 
 a phenyl or benzyl group, optionally substituted on the phenyl ring by:
 1 to 5 halogen atoms, including fluorine or bromine; 
 an OH, SH, OR″ or SR″ radical, R″ having the same definition as above; 
 an amino group optionally mono- or di-substituted by a cyclic or linear aliphatic group having from 1 to 6 carbon atoms; 
 a trifluoromethyl group; 
 an aromatic or heteroaromatic group having 5 or 6 atoms; 
 
 a heteroaromatic group having 5 or 6 atoms, containing 1 or 2 heteroatom(s) selected from oxygen, nitrogen or sulphur, wherein the sulphur and nitrogen atoms may be oxidized in S-oxide or N-oxide form; 
 a methylene substituted by an aromatic or saturated heterocycle having 5 or 6 atoms, the heteroatom being an oxygen, a nitrogen or a sulphur, wherein the nitrogen and sulphur atoms may be oxidized in N-oxide or S-oxide form; 
 
 R 3  and R 4  are not simultaneously a hydrogen atom; 
 R 5  and R 6  are each independently:
 a hydrogen atom; 
 a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 carbon atoms; 
 
 R 7  is:
 a hydrogen; 
 a CH 2 COOR′″ or CH(CH 3 )COOR′″ radical, R′″ being:
 a saturated hydrocarbon chain having from 1 to 6 carbon atoms, optionally substituted by a C 1  to C 3  alkoxy group; 
 a C 5  to C 8  cycloalkyl group; 
 a heteroaromatic phenyl, benzyl or alkyl group; 
 
 a CH(R)O—C(O)OR′ or CH(R)OC(O)R′ group wherein R and R′ have the same definitions as above; 
 
 
       or a pharmaceutically acceptable salt of the compounds for adapted use in a treatment and/or prevention of eye pain. 
     
     
         2 . The compound according to  claim 1 , preventing or relieving eye pain, including dry eye syndrome. 
     
     
         3 . The compound according to  claim 1 , preventing or treating corneal neuropathic pain, including neuropathic hyperalgesia. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is an (acyloxy)alkyl carbamate group —C(═O)—O—C(R)(R′)—OC(═O)—R″. 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is a —C(═O)—O—CHMe-OC(═O)—CHMe 2  group. 
     
     
         6 . The compound according to  claim 1 , wherein R 3  is a hydrogen atom. 
     
     
         7 . The compound according to  claim 1 , wherein R 4  is benzyl group optionally substituted by 1 to 5 halogen atom(s) wherein fluorine or bromine, a phenyl or a 5- or 6-member heteroaromatic group. 
     
     
         8 . The compound according to  claim 1 , wherein R 5  is a hydrogen atom. 
     
     
         9 . The compound according to  claim 1 , wherein R 6  is an alkyl group such as a methyl group. 
     
     
         10 . The compound according to  claim 1 , wherein R 7  is a hydrogen atom. 
     
     
         11 . The compound according to  claim 1 , wherein it is selected from the following compounds:
 2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(1-isobutyryloxy-ethoxycarbonylamino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid benzyl ester:   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(1-isobutyryloxy-ethoxycarbonylamino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid;   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(1-isobutyryloxy-ethoxycarbonylamino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid ethyl ester;   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(1-isobutyryloxy-ethoxycarbonylamino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid ethoxycarbonyloxy ester;   2-(2-(4-Bromo-benzyl)-3-{hydroxy-[1-(1-isobutyryloxy-ethoxycarbonylamino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid benzyl ester;   2-(2-(4-Bromo-benzyl)-3-{hydroxy-[1-(1-isobutyryloxy-ethoxycarbonylamino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid;   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid benzyl ester;   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid;   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(1 amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid ethyl ester;   2-(2-Biphenyl-4-ylmethyl-3-{hydroxy-[1-(amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid ethoxycarbonyloxy ester;   2-(2-(4-Bromo-benzyl)-3-{hydroxy-[1-(amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid benzyl ester;   2-(2-(4-Bromo-benzyl)-3-{hydroxy-[1-(amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid;   2-(2-(4-Bromo-benzyl)-3-{hydroxy-[1-(amino)-ethyl]-phosphinoyl}-propionylamino)-propionic acid ethyl ester.   
     
     
         12 . The compound according to  claim 1 , formulated as an ophthalmic composition comprising one of: eye drops, ophthalmic ointments, ophthalmic gels, or ophthalmic inserts. 
     
     
         13 . The compound according to  claim 12 , wherein the ophthalmic composition comprises from 0.01% to 3% (weight/volume) of the compound of formula (I). 
     
     
         14 . The compound according to  claim 12 , wherein the ophthalmic composition is an aqueous solution having a pH in the range from 5.5 to 8. 
     
     
         15 . The compound according to  claim 12 , wherein the ophthalmic composition further comprises cyclodextrin, including one of: hydroxypropyl beta-cyclodextrin or sulphobutyl ether beta-cyclodextrin, or sodium polystyrene sulphonate.