MXPA00011843A - Aza-heterocyclic compounds used to treat neurological disorders and hair loss - Google Patents

Abstract

This invention relates to novel N-heterocyclic carboxylic acids and carboxylic acid isosteres represented by formula (I), their preparation and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, and for treating alopecia and promoting hair growth. In said formula, n is 1-3;X is either O or S;R1 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, aryl, heteroaryl, carboncycle, or heterocycle;D is a bond, or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl;R is as defined in the application.

Description

CARBOXYLIC ACIDS AND ISOSTEROS OF CARBOXYLIC ACID OF N-HETEROCICLIC COMPOUNDS RELATED REQUESTS DATA This application is a continuation in part of the patent application E.U.A. Serial No. 60 / 087,788 for Hamilton et al., Entitled "Carboxylic Acids and Carboxylic Acid Isosteres of N-Heterocyclic Compounds", filed on June 3, 1988, of the patent application E.U.A. Serial No. 60 / 101,077 for Hamilton et al., Entitled "Carboxylic Acids and Carboxylic Acids Isosteres of N-Heterocyclic Compounds", filed September 18, 1998.

BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION This invention relates to carboxylic acid and carboxylic acid isosterers of N-heterocyclic compounds, their preparation and use to treat neurological disorders including physically damaged nerves and neurodegenerative diseases, and to treat alopecia and to promote hair growth. 2. DESCRIPTION OF THE BACKGROUND TECHNIQUE It has been discovered that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate the growth of neurites in PC12 cells and in sensory nerves, ie dorsal root ganglion cells (DRGs). Lyons et al., Proc. of Nati. Acad. Sci., 1994, vol. 91, pages 3191-3195. In experiments with intact animals, compound FK506 has been shown to stimulate nerve regeneration subsequent to facial nerve damage and results in functional recovery in animals with sciatic nerve injuries. Several neurotrophic factors have been identified that affect populations of specific neurons in the central nervous system. For example, it has been hypothesized that Alzheimer's disease results from a decrease or loss of neuronal growth factor (NGF). Therefore it has been proposed to treat patients suffering from Alzheimer's disease with exogenous neuronal growth factor or with other neurotrophic proteins such as neuronal factor obtained from brain (BDNF), neuronal factor obtained from glia, ciliary neurotrophic factor and neurotropin-3 to increase the survival of degenerating neuron populations. The clinical application of these proteins in various states of neurological disease is hampered by difficulties in the supply and bioavailability of large proteins towards targets in the nervous system. On the other hand, immunosuppressive drugs with neurotrophic activity are relatively small and show excellent bodysponllility and specificity. However, when administered chronically, the immunosuppressants exhibit a number of potentially serious side effects including nephrotoxicity, such as difficulty in glomerular filtration and irreversible interstitial fibrosis (Kopp et al., 1991, J. Am. Soc. Nephrol. 1: 162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina such as non-localized headaches (De Groen et al., 1987, N. Engl. J. Med. 317: 861); and vascular hypertension with complications resulting therefrom (Kahan et al., 1989 N. Engl. J. Med. 321: 1725). Accordingly, there is a need for small molecule compounds that are useful for neurotrophic effects and for treating neurodegenerative disorders. Hair loss occurs in a variety of situations. These situations include male pattern baldness, alopecia senilis, alopecia areata, diseases accompanied by skin lesions or tumors, and systemic disorders such as nutrition disorders and internal secretion disorders. The mechanisms that cause hair loss are very complicated, but in some cases they can be attributed to aging, genetic disposition, the activation of male hormones, loss of blood supply to hair follicles and abnormalities of the scalp.

The immunosuppressive drugs FK506, rapamycin, and cyclosporin are well known as potent T cell-specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol., 1995, 104 , 523-525) and cyclosporin (Iwabuchi et al., J. Invest. Sci., 1995, 9, 64-69) stimulate hair growth in a dose-dependent manner. It is known that a form of hair loss, alopecia areata, is associated with autoimmune activities; therefore, it is expected that immunomodulatory compounds administered topically demonstrate efficacy in treating that type of hair loss. The hair growth stimulating effects of FK506 have been the subject of an international patent presentation covering FK506 and structures related thereto for the stimulation of hair growth (Honbo et al., EP 0 423 714 A2). Honbo et al., Describe the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as agents that revitalize the hair. The effects of hair growth and revitalization of FK506 and related agents are described in numerous US patents (Goulet et al., US Patent No. 5,258,389, Luly et al., US Patent No. 5,457,111; Goulet et al., Patent. US No. 5,532,248, Goulet et al., US Patent No. 5,189,042, and Ok et al., US Patent No. 5,208,241, Rupprecht et al., US Patent No. 5,284,840, Organ et al., US Patent No. 5,284,877). .

These patents claim compounds related to FK506. Although these do not claim methods to revitalize hair, they describe the known use of FK506 to affect hair growth. Similar to FK506 (and the variations claimed in the Honbo et al. Patent), the compounds claimed in these patents are relatively large. Furthermore, the patents cited refer to immunomodulatory compounds that are used in related autoimmune diseases, for which the efficacy of FK506 is well known. Other patents of E.U.A. describe the use of cyclosporine and related compounds for the revitalization of hair (Hauer et al., U.S. Patent No. 5,342,625, Eberle, U.S. Patent No. 5,284,826, Hewitt et al., U.S. Patent No. 4,996,193). These patents also refer to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressant compounds for hair growth. However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for small molecule compounds that are useful as compounds for revitalizing the hair.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the surprising discovery that N-heterocyclic compounds containing a carboxylic acid or carboxylic acid portion of carboxylic acid may be useful for treating neurodegenerative disorders and for treating alopecia and related hair loss disorders. Accordingly, a novel class of compounds containing an acid portion or an isostere thereof bound to the carbon of the 2-position of the N-heterocyclic ring is provided. These compounds stimulate the regeneration and growth of neurons and as such are useful for treating neurological disorders and neurodegenerative disorders. These compounds also promote hair growth and as such are useful for treating hair loss disorders. A preferred feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity and / or are non-immunosuppressive. A preferred embodiment of this invention is a compound of formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain C1-C9 alkyl, straight or branched chain C2-Cg alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or a straight or branched chain C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 8 alkynyl; R2 is a carboxylic acid or a carboxylic acid isostere; and wherein said alkyl, alkenyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents that are selected from R3 and Z, wherein R3 and Z are independently hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain C -? - C6 alkyl, alkenyl or straight or branched chain C2-Cβ alkynyl, aryl, aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain C1-C9 alkyl or straight chain C2-C9 alkenyl or branched; or a pharmaceutically acceptable salt, ester, or solvate thereof; with the proviso that: when n = 1, and D is a bond, and R2 is COOH, then R1 is not straight or branched chain C? -C9 alkyl, straight or branched chain C2-Cg alkenyl, cycloalkyl Cs-C, Cs-C7 cycloalkenyl, phenylamine, 2- (3,4-dichlorophenyl) ethyl, hydroxy, ethoxy, benzyl, or Ar-i, wherein A is 1-naphthyl, 2-naphthyl, 2-indolyl , 3-indolyl, 2-furyl, 3-furyl, 2-thiazoyl, 2-thienyl, 3-thienyl, 1-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, and wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar-i are optionally substituted with one or more substituents which are selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, straight or branched chain C, -C9 alkyl, C2 alkenyl -C9 straight or branched chain, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, COOH, and amino; with the proviso further that: when n = 1, and D is a bond, and R2 is the carboxylic acid isostere -CONZ (R3), and Z is hydrogen or C? -C6 alkyl, and R3 is phenyl, or C2-C6 straight or branched chain alkyl or alkenyl, wherein said alkyl is unsubstituted or substituted at one or more positions with Ar2 as defined below, C3-Cß cycloalkyl, cycloalkyl connected by methyl or an alkyl chain or straight or branched chain C 2 -C 6 alkenyl, C 1 -C 4 alkyl ester, or Ar 3 wherein Ar 3 is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2- thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, having 1 to 3 substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, straight or branched Ci-Cß alkyl, straight or branched C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, C 2 -C alkenyloxy, phenoxy 1, benzyloxy and amino; wherein said alkyl ester is optionally substituted with phenyl; or R3 is the fragment: wherein R4 is selected from the group consisting of straight or branched chain C1-C9 alkyl optionally substituted with C3-C9 cycloalkyl, benzyl, or Ar2 as defined below, and wherein R2 is COOZ or CONR6, wherein R6 is selected from the group consisting of hydrogen, straight or branched Ci-Cβ alkyl and straight or branched C2-C6 alkenyl, and wherein R5 is selected from the group consisting of phenyl, benzyl, straight Ci-Ce alkyl or branched and straight or branched C2-Cß alkenyl, wherein said alkyl or alkenyl is optionally substituted with phenyl; then R1 is not straight or branched chain C9 alkyl, straight or branched chain C2-C9 alkenyl, substituted thiophene, or C1-C4 alkoxy, wherein said alkyl or alkenyl is optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C cycloalkenyl, or Ar2, wherein Ar2 is defined later, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C, -C or alldyl alkenyl, and where Ar 2 is 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-tylnyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, which have from 1 to 3 substituents which are selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, branched straight C6 alkyl, straight branched C2-C6 alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy , phenoxy, benzyloxy and amino; with the proviso further that: when n = 1, and X is O, and D is a bond, and R2 is -CONH2, then R1 is not methyl, ethyl, isopropyl, isobutyl, isopentyl, 4-methylpentyl, indolyl, phenyl or hydroxyphenyl; with the proviso also that: when n = 1, and X is O, and D is a bond, and R2 is cyano, then R1 is not methyl; with the proviso also that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3), and R1 is ethoxy, then R3 or Z is not phenyl substituted with halogen; with the proviso further that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3) and R1 is thiophene or tetrahydro-propanoxy, or substituted methoxy, then R3 or Z is not ethyl substituted with C 1 -C 4 alkyl ester; with the proviso that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3) and R1 is ethoxy, then R3 or Z is not 4-chlorophenyl; with the proviso further that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3) and R1 is cyclohexyl, then R3 or Z is not ethyl or propyl substituted with phenyl; with the proviso further that: when D is CH2, then R2 is not -OMe, -NHMe, or -NHcyclichexyl substituted; with the proviso further that: when D is CH2, and R2 is -OH, then R1 is not phenyl or pyrrolidinemethanol; with the proviso that: when n = 2, and X is O, and D is a bond, and R2 is COOH, then R1 is not methyl, tert-butyl, 1,1-dimethyl-2-methyl- propyl, 1,1-dimethyl-propyl, methoxy, ethoxy, phenyl, C 1 -C 4 alkyl substituted with tetrahydropyranoxy, 1-methy1-1-methoxyamide, 1-methylcyclohexyl, 3-iodophenyl, 3-methyl-cyclopentyl ester, 1,1-d-methyl-6-phenyl-hex-3,5-dioxyl, or trimethoxyphenyl. Preferred embodiments of this invention are those in which R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said ring structure is optionally substituted with R3 in or more positions. Especially preferred embodiments of this invention are those in which R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in or more positions. Another preferred embodiment of this invention is in which R2 is selected from the group consisting of -COOH, -SO3H, -SO2HNR3, -P02 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3 , -NHCOR3, -N (R3) 2 > -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN. Preferred embodiments of this invention are: (2S) -1- (1, 2-d-oxo-3,3-dimethylpentyl) -2-hydroxymethylpyrrolidine; (2S) -1- (1, 2-dioxo-3,3-dimethylpentyl) -2-pyrrolidintetrazole; (2S) -1- (1,2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarbonitrile; and (2S) -1- (1, 2-dioxo-3,3-dimethylpentyl) -2-aminocarbonylpiperidine. Another preferred embodiment of this invention is a pharmaceutical composition containing: an effective amount of a compound of the formula (I); and a pharmaceutically appropriate or acceptable vehicle. For neurotrophic compositions, a neurotrophic factor different from that of formula (I) in the composition may also be administered or included in some other form. Another preferred embodiment of the invention is a method that promotes the regeneration and growth of neurons in mammals, which comprises administering to a mammal an effective amount of a carboxylic acid or isostere of N-heterocyclic carboxylic acid. Another preferred embodiment of the invention is a method for treating a neurological disorder in an animal, comprising administering to an animal an effective amount of a carboxylic acid or N-heterocyclic carboxylic acid ester to stimulate the growth of damaged peripheral nerves or to promote the regeneration of neurons.

Even another preferred embodiment of the invention is a method for preventing neurodegeneration in an animal, which comprises administering to an animal an effective amount of a carboxylic acid or isostere of N-heterocyclic carboxylic acid. Even another preferred embodiment of the invention is a method for treating alopecia or promoting hair growth in an animal, comprising administering to an animal an effective amount of a carboxylic acid or isostere of N-heterocyclic carboxylic acid.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photograph of 6 C57 black mice before being shaved for the hair regeneration experiment. Figure 2 is a photograph of mice treated with a vehicle after 6 weeks. Figure 2 shows that less than 3% of the affected area is covered with new hair growth when the vehicle is administered (control). Figure 3 is a bar graph illustrating relative hair growth in shaved mice treated with carboxylic acids or N-heterocyclic carboxylic acid isosteres at concentrations of 1 μmol per milliliter 3 times per week. Hair growth was evaluated after 14 days of treatment.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" means a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms. For example, the straight or branched C-? -C6 alkyl hydrocarbon chain contains from 1 to 6 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, n-pentyl, n-hexyl and the like. It is also contemplated within the scope of the present invention that "alkyl" may also refer to a hydrocarbon chain in which any of the carbon atoms of said alkyl is optionally replaced with O, NH, S, or SO2. For example, n-pentyl carbon 2 may be replaced with O to form propyloxymethyl. "Alkenyl" means a branched or unbranched, unsaturated hydrocarbon chain, comprising a designated number of carbon atoms. For example, the straight or branched C2-C2 hydrocarbon alkenyl chain contains 2 to 6 carbon atoms having at least one double bond, and includes but is not limited to substituents such as ethenyl, propenyl, isopropenyl, butenyl,! sobutenyl, terbutenyl, n-pentenyl, n-hexenyl, and the like. It is also contemplated within the scope of the invention that "alkenyl" can refer to an unsaturated hydrocarbon chain in which any of the carbon atoms of said alkenyl is optionally substituted with O, NH, S or SO2. For example, the carbon atom 2 of the 4-pentene can be substituted with O to form (2-propen) oxymethyl. "Alkoxy" means the group -OR in which R is alkyl as defined in the present invention. Preferably, R is a branched or unbranched saturated hydrocarbon chain containing from 1 to 6 carbon atoms. Specifically, the term "carbocycle" refers to an organic cyclic portion in which the cyclic base structure consists solely of carbon atoms while the term "heterocyclic" refers to an organic cyclic portion in which the cyclic base structure contains one or more heteroatoms that are selected from nitrogen, oxygen or sulfur and which may or may not include carbon atoms. Therefore, the term "carbocycle" refers to a carbocyclic portion containing the indicated number of carbon atoms. The term "C3-C8 cycloalkyl", therefore, refers to an organic cyclic substituent in which 3 to 8 carbon atoms form a ring of three, four, five, six, seven or eight links, including, example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. As used in the present invention, "carbocycle" may also refer to two or more cyclic ring systems that are fused to form, for example bicyclic, tricyclic substituents or other similar bridge substituents (for example adamantyl). "Aryl" refers to an aromatic carbocyclic group having a single ring, for example a phenyl ring; multiple rings, for example biphenyl; or multiple condensed rings in which at least one ring is aromatic, for example naphthyl, 1, 2,3,4-tetrahydronaphthyl, anthryl, or phenanthryl, which may be unsubstituted or substituted with one or more other substituents as defined above. Substituents attached to a phenyl ring portion of an aryl portion in the compounds of formula (I) may be configured in the ortho-, meta-, or para- orientations. Examples of typical aryl portions included in the field of the present invention may include, but are not limited to, the following: "Aralkyl" refers to an alkyl or alkylene (alkenyl) chain which is substituted with aryl, heteroaryl, carbocycle or heterocycle, or alternatively one or more aryl (s), heteroaryl (s), carbocycle (s) or heterocycle (s) which are / are substituted with alkyl or alkenyl, ie "alkyl / alkylene which is substituted with Ar" or "Ar which is substituted with alkyl / alkylene". "Heterocycle" refers to a saturated, unsaturated or aromatic carbocyclic group having a single ring, multiple rings or condensed multiple rings, and having at least one heteroatom such as nitrogen, oxygen or sulfur within at least one of the Rings. "Heteroaryl" refers to a heterocycle in which at least one ring is aromatic. Any of the heterocyclic or heteroaryl groups may be unsubstituted or optionally substituted with one or more groups as defined above. In addition, the bi- or tricyclic heteroaryl portions may comprise at least one ring which is either fully saturated or partially saturated. As will be appreciated by one skilled in the art, such heterocyclic portions may exist in various isomeric forms, all of which are encompassed by the present invention. For example a 1, 3,5-triazine portion is isomeric to a 1, 2,4-triazine group. Such position isomers should be considered within the scope of the present invention. Likewise, the heterocyclic or heteroaryl groups may be linked to other portions in the compounds of the present invention. The point or points of attachment to these other portions should not be considered as limitations on the field of the invention. Therefore, by way of example, a pyridyl portion can be attached to other groups through the 2-, 3-, or 4- position of the pyridyl group. All of such configurations should be considered as within the scope of the present invention. Examples of heterocyclic or heteroaryl portions included in the field of the present invention may include, but are not limited to, the following: ?? "Halogen" means at least one fluorine, chlorine, bromine or iodine moiety. The term "pharmaceutically acceptable salt, ester or solvate" refers to salts, esters or solvates of the present compounds which possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. The salt, ester or solvates can be formed with inorganic or organic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanpropionate, digluconate, dodecylisulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodohydrate, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonate, naphtylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. The basic salt, ester or solvate includes the ammonium salts, the alkali metal salts such as the lithium, sodium and potassium salts, the alkaline earth metal salts such as the calcium and magnesium salts, the salt with organic bases such as the salts of dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc. In addition, the nitrogen groups can be quatemized with agents such as: 1) lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; 2) dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, 3) long chain alkyls such as decyl, lauryl, myristyl and stearyl substituted with one or more halides such as chloride, bromide and iodide; and 4) aralkyl halides such as benzyl bromide and phenethyl bromide and others. The compounds of this invention can possess at least one asymmetric center and can therefore be produced as mixtures of stereoisomers or as individual enantiomers or diastereomers. Individual stereoisomers can be obtained by using an optically active starting material, resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of synthesis, or by resolution of the compound of formula (I). It is understood that individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the field of the present invention. The S-stereoisomer in atom 1 of formula (I) is one of the most preferred embodiments of the invention. "Stereoisomers" are isomers that differ only in the way that atoms are arranged in space. The "isomers" are different compounds that have the same molecular formula and include cyclic isomers such as (4) indole and other isomeric forms of the cyclic portions. "Enantiomers" are a pair of stereoisomers that are mirror images of one another that can not be superimposed. "Diastereomers" are stereoisomers that are not mirror images of one another. "Racemic mixture" means a mixture containing equal parts of enantiomers. "Non-racemic mixture" is a mixture containing individual parts of individual enantiomers or stereoisomers. The "isosterers" are different compounds that have different molecular formulas but show the same or similar properties. For example, tetrazole is a carboxylic acid steroid because it limits the properties of carboxylic acid even though both have very different molecular formulas. Tetrazol is one of the many possible isosteric replacements for carboxylic acid. Other isosteres of the carboxylic acid contemplated by the present invention include -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3 ) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN. In addition, the carboxylic acid isosteres may include carbocycles or 5-7 link heterocycles containing any combination of CH2 | O, S, or N in any chemically stable oxidation state, in which any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of the preferred carbocyclic and heterocyclic isosteres contemplated by this invention. wherein the atoms of said ring structure can optionally be substituted with R3 in one or more positions. The present invention contemplates that when the chemical substituents are added to a carboxylic acid isostere then the compounds of the invention retain the properties of a carboxylic acid isostere. The present invention contemplates that when a carboxylic acid ester is optionally substituted with one or more portions that are selected from R3, then the substitution can not eliminate the isosteric properties of carboxylic acid of the compounds of the invention. The present invention contemplates that the placement of one or more R3 substituents on a carbocyclic or a heterocyclic carboxylic acid steroid in one or more atoms that maintain or maintain or that is / are an integral part of the isosteric acid properties should not be allowed. carboxylic acid of the compounds of the invention, if such or such substituent (s) will destroy the isosteric properties of carboxylic acid of the compound of the invention. Other carboxylic acid isosterers not specifically exemplified or described in this specification are also contemplated by the present invention. It is understood that when chemical substitution is indicated then the chosen chemical substituent will form a sufficiently stable compound. The term "preventing neurodegeneration" as used in the present invention includes the ability to inhibit or prevent neurodegeneration in patients who have been recently diagnosed as suffering from a neurodegenerative disease, or who are at risk of developing a new degenerative disease and to inhibit or prevent further neurodegeneration in patients who in advance suffer from, or who present symptoms of a neurodegenerative disease when the compounds are administered concurrently. The term "treatment" as used in the present invention covers any treatment of a disease and / or condition in an animal, particularly a human, and includes: (i) preventing a disease and / or condition from occurring in a subject who may be predisposed to the disease and / or condition, but who has not yet been diagnosed as having it; (I) inhibit the disease and / or condition, that is, stop its development; or (iii) healing the disease and / or condition, i.e., causing the regression of the disease and / or condition.

The system used to name the compounds of the present invention is shown below, using a compound of the formula I as an example. A compound of the present invention, especially of the formula I, in which n is 1, X is O, D is a bond, Ri is 1,1-dimethylpropyl, and R2 is -CN, is named (2S) -1 - (1 > 2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarbonitrile. "Alopecia" refers to poor hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (baldness with male pattern), toxic alopecia, alopecia senilis, alopecia areata, peeling alopecia and trichotillomania. Alopecia occurs when the hair cycle is disturbed. The most frequent phenomenon is a shortening of hair growth or anagen phase due to the arrest of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles detach from the dermal papilla, and the hair falls out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental tensions, hormonal problems and the side effects of drugs. "Hair cycle" refers to the life cycle of the hair follicles, and includes three phases: (1) the anagen phase, the period of active growth of the hair which, in regard to the hair of the scalp, lasts approximately three to five years; (2) the catagen phase, the period when the growth stops and the follicle atrophies which, in regard to the hair of the scalp, lasts from one to two weeks; and (3) the telogen phase, the resting period when the hair progressively separates and finally falls, which, in regard to the hair of the scalp, lasts approximately three to four months. Normally between 80 and 90 percent of the follicles are in the anagen phase, less than 1 percent in the catagen phase and the rest being in the telogen phase. In the telogen phase, the hair is of uniform diameter with a slightly bulbous, non-pigmented root. On the contrary, in the anagen phase, the hair has a large and pigmented bulb at its root. "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating or revitalizing hair germination. Treating alopecia "refers to: (i) preventing alopecia in an animal which may be predisposed to develop alopecia, and / or (ii) inhibiting, retarding or reducing alopecia, and / or (i) promoting hair growth. and / or (iv) prolonging the anagen phase of the hair cycle, and / or (v) converting villous hair to grow as terminal hair.The terminal hair is thick, pigmented, and long hair in which the follicle bulb Hair is deeply seated in the dermis, hair on the other hand is fine, thin, short, non-pigmented hair in which the hair bulb is located superficially in the dermis.As the alopecia progresses, the hair changes terminal type The term "neurotrophic" as used in the present invention includes without limitation the ability to stimulate neuronal growth or regeneration and / or the ability to prevent or treat neurodegeneration. "munosuppressant" refers to the inability of the compounds of the present invention to induce an immune response when compared to a control such as FK506 or cyclosporin A. Tests to determine immunosuppression are well known to those skilled in the art. Specific non-limiting examples of well-known tests include PMA and OKT3 tests in which mitogens are used to stimulate the proliferation of peripheral human blood lymphocytes (PBC). The compounds added to such test systems are evaluated with respect to their ability to inhibit such proliferation.

COMPOSITIONS OF THE INVENTION The present invention relates to the surprise discovery that carboxylic acid compounds or carboxylic acid isosteres are neurotrophic compounds and. They can be used to treat alopecia. A preferred feature of the compounds of the present invention is that they do not exert significant immunosuppressive activity. Preferred compounds of the present invention contain portions of carboxylic acid and other base substitutions for the carboxylic acid portions of which several examples are specified in the present invention. Other isosteric replacements for the carboxylic acid moieties, known to those skilled in the art of medicinal chemistry, are within the scope of the invention if not otherwise specified. The compounds of this invention can be administered periodically to a patient undergoing treatment for neurological disorders or for other reasons in which it is desired to stimulate the regeneration and growth of neurons, such as in the various peripheral neuropathic and neuropathic disorders that are relate to neurodegeneration. The compounds of this invention can also be administered to mammals other than humans for the treatment of various neurological disorders in mammals. The novel compounds of the present invention possess an excellent degree of neurotrophic activity. This activity is useful in the stimulation of damaged neurons, in the promotion of neuron regeneration, in the prevention of neurodegeneration and in the treatment of several neurological disorders that are known to be associated with the degeneration of neurons and peripheral neuropathies. Neurological disorders that can be treated include but are not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscle atrophy, progressive bulbar muscular inherited atrophy, disc syndromes of the vertebra with hernia, broken or prolapsed, cervical spondylosis, plexus disorders, syndromes of destruction of the thoracic outlet, peripheral neuropathies such as those caused by lead, dapsone, ticks, porphyria, or Gullain-Barré syndrome, Alzheimer's disease, and Parkinson's disease. The above description regarding the utility and administration of the compounds of the present invention also applies to the pharmaceutical compositions of the present invention. The term "pharmaceutically acceptable carrier" as used in the present invention refers to any carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surface active agent, coloring, flavoring or sweetening. For these purposes the compounds of the present invention can be administered orally, parenterally, by spraying for inhalation, topically, rectally, nasally, buccally, vaginally or by a deposit implanted in the mouth. dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used in the present invention includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intraextemal and intracranial injection or infusion techniques. For oral administration, the compounds of the present invention can be provided in any suitable dosage form known in the art. For example, the compositions can be incorporated into tablets, powders, granules, beads, chewable tablets, capsules, liquids, suspensions or aqueous solutions, or similar dosage forms, using conventional equipment and techniques known in the art. Tablet dosage forms are preferred. The tablets may contain carriers such as lactose and corn starch and / or lubricating agents such as magnesium stearate. The capsules may contain diluents including lactose and dried corn starch. The aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient When preparing the dosage form that incorporates the compositions of the invention, the compounds can also be combined with conventional excipients such as binders, including gelatin, pregelatinized starch and the like; lubricants, such as hydrogenated vegetable oil, stearic acid and the like; diluents, such as lactose, mannose, and sucrose; disintegrants, such as carboxymethylcellulose and sodium starch glycolate; suspending agents such as povidone, polyvinyl alcohol and the like; absorbers such as silicon dioxide; preservatives, such as methyl paraben, propyl paraben and sodium benzoate; surfactants such as sodium lauryl sulfate, polysorbate 80 and the like; dyes such as FD &C dyes and the like; flavors; and sweeteners. The compositions and methods of the invention can also use controlled release technology. Thus, for example, the compounds of the invention can be incorporated into a hydrophobic polymer matrix for controlled release over a period of days. Such controlled release films are well known in the art. Particularly preferred systems are transdermal delivery systems. Other examples of polymers commonly used for this purpose that can be used in the present invention include non-degradable ethylene-vinyl acetate copolymer and degradable lactic acid-glycolic acid copolymers which can be used externally or internally. Certain hydrogels such as poly (hydroxyethyl methacrylate) or poly (vinyl alcohol) may also be useful, but for shorter release cycles then the other polymeric release systems are used, such as those mentioned above. To be therapeutically effective as targets of the central nervous system, the compounds of the present invention must readily penetrate the blood-brain barrier when administered peripherally. Compounds that can not penetrate the blood-brain barrier can be administered effectively by an intraventricular or other appropriate delivery system that is suitable for administration to the brain. The compounds of the present invention can be administered in the form of sterile injectable preparations, such as, for example, injectable aqueous or oleaginous suspensions. These suspensions can be formulated in accordance with techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspending media. For this purpose, any combination of non-volatile oil can be used including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, are useful in the preparation of injectables, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain long chain alcohol diluents or dispersants. The compounds of this invention can also be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The compounds of this invention can also be administered topically, especially when the conditions they face for treatment involve easily accessible areas or organs by topical application, including neurological disorders of the eye, skin or lower intestinal tract. Appropriate topical formulations are easily prepared for each of these areas. For topical application to the eye, or ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic saline solution, sterile, with adjusted pH or, preferably, as solutions in sterile saline isotonic solution, with adjusted pH, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic uses the compounds can be formulated into an ointment such as petrolatum. For topical application to the skin, the compounds may be formulated in an appropriate ointment containing the compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, a compound polyoxyethylene-polyoxypropylene, emulsifying wax and water. Alternatively, the compounds may be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, wax ethyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Topical application for the lower intestinal tract can be done in a rectal suppository formulation (see above) or in an appropriate formulation for enema. Dosage levels of the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful for the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typically, in vitro dose-effect results provide useful guidance on appropriate dosages for administration to patients. Studies in animal models are also useful. Considerations for determining appropriate dose levels are well known in the art. However, it is understood that a specific dosage level, for any particular patient, will depend on a variety of factors including the activity of the specific compound used, age, coforal weight, general health condition, sex, diet, time of administration , rate of excretion, combination with drugs and the severity of the particular disease that is being treated and the manner of administration. To effectively treat alopecia or promote hair growth, the compounds used in the methods and pharmaceutical compositions of the invention should easily affect the target areas. For these purposes, the compounds are preferably administered topically to the skin. For topical application to the skin, the compounds may be formulated as suitable ointments containing the suspended or dissolved compounds in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, compound of polyoxyethylene-polyoxypropylene, emulsifying wax and water. Alternatively, the compounds may be formulated as appropriate lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax , cetearyl alcohol, 2-octylodecanol, benzyl alcohol and water. The compounds can be administered with other agents that revitalize the hair. The specific dosage levels for the other agents that revitalize the hair will depend on the factors previously indicated and the effectiveness of the combination of drugs. Other routes of administration known in the pharmaceutical art are also contemplated by this invention. The specific embodiments of the compounds of the invention are presented in tables I, II, and III. The present invention contemplates using the compounds of the following Tables I, II, and III, for use in compositions and methods for preventing and / or treating a neurological disorder in an animal, and for use in compositions and methods for treating Alopecia and promote hair growth in an animal, and all other uses suggested in this specification.

TABLE I D is a link and R2 is COOH, TABLE II TABLE III Specific embodiments of the present invention also include compound 139: Compound 139 The carboxylic and phosphate acids of additional N-heterocyclic compounds claimed or compared, which also exhibit the well-known neurotrophic and hair growth effects of the present invention are shown below in Table IV: TABLE IV Comp. n D R2 Letter / number A / 137 1 Link COOH 1,2-dioxoethyl 1,1-dimethylpropyl B / 138 2 Link COOH 1, 2-dioxoethyl 1,1-dimethylpropyl C 1 Bond COOH SO2 Benzyl D / 26 1 CH2 OH 1,2-dioxoethyl 1,1-dimethylpropyl E / 30 1 Link T Teettrraazzool 1, 2-dioxoethyl 1,1-dimethylpropyl F / 29 1 Link -CN 1, 2-dioxoethyl 1,1-dimethylpropyl G / 35 2 Link CONH5 1, 2-dioxoethyl 1,1-dimethylpropyl where Y and Z are both carbon for the compounds A-G H 1 COOH 1,2-dioxoethyl 1,1-dimethylpropyl linkage I 1 COOH 1, 2-dioxoethyl 1,1-dimethylpropyl linkage where Z is S for compound H and where Y is S for compound I.

PHARMACEUTICAL COMPOSITIONS OF THE PRESENT INVENTION The present invention relates to a pharmaceutical composition comprising: (i) an effective amount of a carboxylic acid compound or N-hetrocyclic carboxylic acid isostere; and (ii) a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a carboxylic acid compound or N-heterocyclic carboxylic acid ester to treat neurodegenerative diseases, neurological disorders and nerve damage, or to promote growth of nerves in an animal; and (i) a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a carboxylic acid or N-heterocyclic carboxylic acid compound to treat alopecia or to promote hair growth in an animal, and ( I) a pharmaceutically acceptable vehicle. The compounds can be administered with other neurotrophic agents such as neurotrophic growth factor, brain obtained growth factor, growth factor obtained from the glia, ciliary neurotrophic factor, insuycinic growth factor, and truncated active derivatives thereof, factor of acid growth of fibroblasts, basic growth factor of fibroblasts, growth factors obtained from platelets, neurotropin-3 and neurotropin 4/5. The level of dosage of other neurotrophic drugs will depend on the previously indicated factors and on the neurotrophic effectiveness of the combination of drugs.

METHODS OF THE PRESENT INVENTION The present invention relates to the use of any of the compounds observed in Tables I, II, III, IV, and other compounds modalized therein, in the preparation of a medicament for the treatment of a disease such as peripheral neuropathy caused by physical damage or state of illness, physical damage to the brain, physical damage to the spinal cord, stroke associated with damage to the brain, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The present invention also relates to the use of carboxylic acid compounds and carboxylic acid isosteres to treat the aforementioned neuropathies, neurological disorders and neurological damage. The present invention also relates to a method for treating alopecia or to promote hair growth in an animal, comprising administering to said animal an effective amount of a carboxylic acid or isostere of N-heterocyclic carboxylic acid. The present invention also relates to the use of the compounds and compositions of the invention in the preparation of a medicament for the treatment of alopecia or to promote hair growth in an animal. The method of the invention is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systemic disorders such as nutrition disorders and disorders of internal secretion. However, it is understood that a specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound used, age, coforal weight, general health status, sex, diet, time of administration, rate of excretion, combination of drugs and the severity of the particular disease or disorder being treated and the manner of administration. MPTP model for Parkinson's disease in mice The lesion of dopaminergic neurons with MPTP in mice was used as an animal model of Parkinson's disease. They were administered, by i.p., to white mice CT1 male of 4 weeks of age, 30 mg / kg of MPTP for 5 days. The compounds of the invention (4 mg / kg), or vehicle, were administered s.c. together with the MPTP for 5 days, as well as for an additional period of 5 days after cessation of MPTP treatment. At 18 days after the MPTP treatment, the animals were sacrificed and the striatum was excised and homogenized. Immunostaining was performed on the sagittal and coronary sections of the brain using anti-tyrosine hydroxylase Ig to quantify the survival and recovery of dopaminergic neurons. In animals treated with MPTP and vehicle, a substantial loss of functional dopaminergic terminals was observed compared to intact animals. In another protocol, the test compounds were administered only after the lesions induced with MPTP. Therefore, after the animals were treated with MPTP for 5 days, an additional 3 days passed before starting the drug treatment orally on the eighth day. The animals were treated with the compounds of the invention (0.4 mg / kg), administered orally, once a day for 5 days in total. On day 18, the animals were sacrificed and analyzed as described above. Table IV presents the percent recovery of the dopaminergic neurons in the first paradigm (concurrent dose) in animals receiving the carboxylic acid or carboxylic acid steroid compounds of the present invention. Table V, below, shows the notorious neuroregenerative effects of the carboxylic acid or carboxylic acid isostere compounds which illustrate the neurotrophic capacity of the carboxylic acid esters as a class that shows that the injured animals receiving the compounds of carboxylic acid or carboxylic acid isostere provide a remarkable recovery of dopaminergic neurons stained with TH.

TABLE V Neurodegenerative model with MPTP % recovery Compound A 26.7% Compound B ND Compound C 24.4% Compound D 23.2% Compound E 19.6% Compound F 34.1% Compound G 46.5% Compound H 14.0% Compound I ND The percent density of innervation of the striatum in brain sections was quantified with an anti-throsarin hydroxylase immunoglobulin, which serves to indicate functional dopaminergic neurons. The density of innervation of the striatum of 23% for the animals pre-treated with only one vehicle and to which a vehicle was administered orally during the treatment, is a normal Intact striated body tissue indicator. The density of innervation of the striatum is reduced to 5% for animals pretreated with MPTP and to which a vehicle is administered orally during treatment, which indicates the lesion induced by MPTP. Surprisingly, the innervation density of the striatum is increased 8-13% for animals pretreated with MPTP and to which 0.4 mg / kg of a compound of the invention is administered orally during treatment, which indicates a substantial regeneration of neurons after the induction of lesions obtained with MPTP. The following examples are illustrative of the preferred embodiments of the invention and should not be considered as limiting the invention to them. All the molecular weights of the polymers are molecular weights on average. All percentages are based on the weight percent of the final delivery system or formulation prepared unless otherwise indicated and all totals equal 100% by weight.

EXAMPLES The compounds of the invention can be prepared by a variety of synthetic sequences using established chemical transformations. A general route for the compounds of the present invention is described in Scheme I. The N-glyoxylproline derivatives can be prepared by reacting L-proline methyl ester with methloxalyl chloride as shown in Scheme I. The resulting oxamates are they can react with a variety of carbon nucleophiles to obtain the compounds used in the present invention.

SCHEME I EXAMPLE 1 (COMPOUND 137) Synthesis of (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate Synthesis of (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidine-carboxylate A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmol) in dry methylene chloride it was cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmoles, 2.1 equivalents). After stirring the solution formed under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g, 26.12 mmol) in methylene chloride (45 ml) was added dropwise. The resulting mixture was stirred at 0 ° C for 1.5 hours. After filtering to remove the solids, the organic phase was washed with water, dried with MgSO 4 and concentrated. The crude residue was purified on a column with silica gel, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of rotamers of the cis-trans amide; data are given for the trans rotamer: 1 H NMR (CDCl 3): d 1.93 (dm, 2 H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, J = 8.4, 3.3).

Synthesis of methyl (2S) -1- (1,2-d-oxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylate A solution of (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidin- Methyl carboxylate (2.35 g, 10.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled to -78 ° C and treated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for three hours, the mixture was poured into saturated ammonium chloride (100 ml) and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated, and the crude material obtained after removing the solvent was purified on a column with silica gel, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g ( 75%) of the oxamate as a colorless oil. H NMR (CDCl 3): d 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.33 (m, 1 H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J = 8.4, 3.4). c. Synthesis of (2S) -1- (1,2-d¡oxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylic acid A mixture of (2S) -1- (1I2-dioxo-3,3-d-methylpentyl) -2-pyrrolidinecarboxylate Methyl (2.10 g, 8.23 mmol), 1 N LiOH (15 ml), and methanol (50 ml) were stirred at 0 ° C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1N HCl, diluted with water and extracted with 100 ml of methylene chloride. The organic extract was washed with brine and concentrated to give 1.73 g (87%) of white solid which does not need further purification. 1 H NMR (CDCl 3): d 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1 H); 2.25 (m, 1 H); 3.53 (dd, 2H, J = 10.4, 7.3), 4.55 (dd, 1H, J = 8.6, 4.1).

SCHEME II The compounds of the invention containing bridged rings can be synthesized using the above synthesis schemes by substituting the substrates containing the N-heterocyclic ring structures with comparable substrates containing ring structures with bridges.

EXAMPLE 2 Synthesis of (2S) -1 - (1,2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxamide (compound 34) Isobutyl chloroformate (20 mmol, 2.7 ml) was added to a solution containing (2S) -1- (1, 2-d-oxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylic acid (4.89 g, mmoles) (from example 1) in 50 ml of methylene chloride at -10 ° C with stirring. After 5 minutes, ammonia was added dropwise (20 mmoles, 10 ml of a 2 M solution in ethyl alcohol). The reaction was warmed to room temperature after stirring at -10 ° C for 30 minutes. The mixture was diluted with water, and extracted with 200 ml of methylene chloride. The organic extract was concentrated and further purified with silica gel to give 4.0 g of product as a white solid (81.8% yield). 1 H NMR (CDCl 3): d 0.91 (t, 3H, J = 7.5); 1.28 (s, 6H, each); 1.63-1.84 (m, 2H); 1.95-2.22 (m, 3H); 2.46 (m, 1 H); 3.55-3.67 (m, 2H); 4.67 (t, 1H, J = 7.8); 5.51-5.53 (width, 1 H, NH); 6.80 (width, 1 H, NH).

EXAMPLE 3 Synthesis of (2S) -1 - (1,2-dioxo-3,3-dimethylpentiD-2-pyrrolidinecarbonitrile (compound 29) 0.48 ml (5.5 mmol) of oxalyl chloride was added to a solution of 0.465 ml of DMF (6 mmol) in 10 ml of acetonltryl at 0 ° C. Immediately a white precipitate formed and was accompanied by gas evolution. When the reaction was finished, a solution of 1.2 g (5 mmol) of (2S) -1- (1,2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxamide (from Example 2) was added in 2.5. ml of acetonitrile. When the mixture became homogeneous, 0.9 ml (11 mmol) of pyridine was added. After 5 minutes, the mixture was diluted with water and extracted with 200 ml of ethyl acetate. The organic layer was concentrated and further purified with silica gel to give 0.8 g of product as a white solid (72% yield). 1 H NMR (CDCl 3): d 0.87 (t, 3H, J = 7.5); 1.22 (s, 3H); 1.24 (s, 3H); 1.80 (m, 2H); 2.03-2.23 (m, 4H); 3.55 (m, 2H); 4.73 (m, 1 H).

EXAMPLE 4 Synthesis of (2S) -1 - (1,2-dioxo-3,3-dimethylpentyl) -2-pyrrolidintetrazole (compound 30) A mixture of (2S) -1- (1,2-d-oxo-3,3-dimethylpentyl) -2-pyrrolidinecarbonitrile (222 mg, 1 mmol) (from example 3), NaN3 (81 mg , 1.3 mmol) and NH CI (70 mg, 1.3 mmol) in 3 ml of DMF was stirred at 130 ° C for 16 hours. The mixture was concentrated and further purified by silica gel to obtain 200 mg of product as a white solid (75.5% yield). H NMR (CDCl 3): d 0.88 (t, 3H, J = 7.5); 1.22 (s, 6H); 1.68 (m, 2H); 2.05-2.36 (m, 3H); 2.85 (m, 1 H); 3.54 (m, 1 H); 3.75 (m, 1 H); 5.40 (m, 1 H).

EXAMPLE 5 In vivo hair generation test with 6 black C57 mice Six black C57 mice were used to demonstrate the hair revitalization properties of the carboxylic acids or the N-heterocyclic carboxylic acid isosteres. Referring now to Figures 1 and 2 of the drawings, 6 black C57 mice, approximately 7 weeks old, have a shaved area of approximately 5 cm x 5 cm on their hind legs to remove all existing hair. Precautions were taken not to lacerate or scrape the underlying dermal layers. The animals were in the anagen growth phase, as indicated by the pink color of the skin. Referring now to Figure 2, 4 animals were treated per group by topical administration with 20% propylene glycol vehicle (Figure 2) or with FKBP ligands for neuroimmunophilin dissolved in the vehicle. The animals were treated with vehicle or ligands for neuroimmunofilin every 48 hours (3 applications in total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantified by the percentage of the shaved area covered by new hair growth during this period. Figure 2 shows that the animals treated with vehicle presented only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. On the contrary, Figure 3 shows that the animals treated for 2 weeks with the N-heterocyclic carboxylic acid compounds, ie the compound A (137), the compound B (138) and the compound G (35), presented a dramatic hair growth, covering more than 25% of the shaved area in all animals for two of the compounds. Figure 3 shows the relative growth of hair in 6 black C57 mice shaved 14 days after being treated with one of the three carboxylic acids or isosterers of N-heterocyclic carboxylic acid. The mice have a shaved region of 5cm x 5cm on their backs to remove all the hair. Precautions were taken not to lacerate or scrape the underlying dermal layers. The compounds, at a concentration of 1 μmol per milliliter, were carefully applied to the shaved area of the mice (5 mice per group) three times per week. Hair growth was evaluated 14 days after starting treatment with the drug. The relative scale to evaluate hair growth is as follows; 0 = no growth; 1 = start of growth in small tufts; 2 = hair growth covering < 25% of the shaved area; 3 = hair growth covering > 25% of the shaved area, but less than 50% of the shaved area; 4 = hair growth covering > 50% of the shaved area, but less than 75% of the shaved area; 5 = hair growth in the entire shaved area.

EXAMPLE 6 A lotion comprising the following composition can be prepared.

A carboxylic acid or N-heterocyclic carboxylic acid ester, α-tocopherol acetate, ethylene oxide (40 mol) adducts of hydrogenated castor oil, perfume and a dye are added to the 95% ethanol. The resulting mixture is stirred until it dissolves and purified water is added to the mixture to obtain a clear liquid lotion. You can apply 5 ml of the lotion once or twice a day to the site that has marked baldness or alopecia.

EXAMPLE 7 A lotion comprising the following composition shown can be prepared.

A carboxylic acid or N-heterocyclic carboxylic acid isostere, hinokitol, ethylene oxide (40 mol) adducts of hydrogenated castor oil, perfume and a dye are added to the 95% ethanol. The resulting mixture is stirred and purified water is added to the mixture to obtain a clear liquid lotion. The lotion can be applied by spraying one to four times a day to the site that has marked baldness or alopecia.

EXAMPLE 8 An emulsion can be prepared from phase A and phase B comprising the following composition.

Phase A and phase B are heated and melted respectively and maintained at 80 ° C. Then both phases are mixed and cooled with stirring to the normal temperature to obtain an emulsion. The emulsion can be applied by spraying one to four times a day to the site that has baldness or marked alopecia.

EXAMPLE 9 A cream can be prepared from phase A and phase B comprising the following composition.

Phase A is heated and melted, and maintained at 70 ° C. Phase B is added to phase A and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream. The cream can be applied by spraying one to four times a day to the site that has baldness or marked alopecia.

EXAMPLE 10 A liquid comprising the following composition can be prepared.

The polyoxyethylene butyl ether, propylene glycol, polyoxyethylene-hydrogenated castor oil, a carboxylic acid or isostere of N-heterocyclic carboxylic acid and the perfume are added to the ethanol. The resulting mixture is stirred and purified water is added to the mixture to obtain a liquid. The fluid can be applied one to four times a day to the site that has baldness or marked alopecia.

EXAMPLE 11 A shampoo comprising the following composition can be prepared. 69.7 parts of purified water, 5.0 g of sodium lauryl sulfate, 5.0 g of triethanolamine lauryl sulfate, 6.0 g of water are added.

Betaine lauryl dimethylamine acetate. Then a mixture obtained by adding 5.0 g of a carboxylic acid or isostere of N-heterocyclic carboxylic acid, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, stirring, and 0.3 g are added successively. of perfume. The resulting mixture is heated and then cooled to obtain a shampoo. The shampoo can be used on the scalp one to two times per day.

EXAMPLE 12 A patient suffers from alopecia senilis. A carboxylic acid or carboxylic acid N-heterocyclic acid, or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 13 A patient has alopecia with a male pattern. A carboxylic acid or N-heterocyclic carboxylic acid ester or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 14 A patient suffers from alopecia areata. A carboxylic acid or isostere of N-heterocyclic carboxylic acid, or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 15 A patient suffers from hair loss caused by skin lesions. A carboxylic acid or N-heterocyclic carboxylic acid ester or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 16 A patient suffers from hair loss caused by tumors.

The patient may be administered a carboxylic acid or isostere of N-heterocyclic carboxylic acid, or a pharmaceutical composition comprising the same. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 17 A patient suffers from hair loss caused by a systemic disorder, such as a nutrition disorder or an internal secretion disorder. A carboxylic acid or isostere of N-heterocyclic carboxylic acid, or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 18 A patient suffers from hair loss caused by chemotherapy. A carboxylic acid or isostere of N-heterocyclic carboxylic acid, or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 19 A patient suffers from hair loss caused by radiation. A carboxylic acid or isostere of N-heterocyclic carboxylic acid, or a pharmaceutical composition comprising the same can be administered to the patient. It is expected that there will be an increased hair growth after treatment.

EXAMPLE 20 A patient suffers from a neurodegenerative disease. A carboxylic acid or N-heterocyclic carboxylic acid ester or a pharmaceutical composition comprising the same can be administered to the patient. The patient could be expected to improve their condition or recover.

EXAMPLE 21 A patient suffers from a neurological disorder. The patient is administered a carboxylic acid or a carboxylic acid isostere of an N-heterocyclic ring, or the pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 22 A patient suffers from embolism. The patient is administered a carboxylic acid or an isostere of carboxylic acid of an N-heterocyclic ring, or the pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 23 A patient suffers from Parkinson's disease. The patient is administered a carboxylic acid or a carboxylic acid ester of an N-heterocyclic ring, or the pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 24 A patient suffers from Alzheimer's disease. The patient is administered a carboxylic acid or a carboxylic acid ester of an N-heterocyclic ring, or the pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 25 A patient suffers from a peripheral neuropathy. The patient is administered a carboxylic acid or a carboxylic acid isostere of an N-heterocyclic ring, or the pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 26 A patient suffers from amyotrophic lateral sclerosis. The patient is administered a carboxylic acid or a carboxylic acid ester of an N-heterocyclic ring, or the pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 27 A patient suffers from damage to the spine. The patient is administered a carboxylic acid or an isostere of carboxylic acid of an N-heterocyclic ring, or pharmaceutical compositions comprising them. The patient could be expected to improve their condition or recover.

EXAMPLE 28 A patient is at risk of suffering from a neurodegenerative disease or a neurological disorder. The patient is administered, prophylactically, a carboxylic acid or a carboxylic acid isostere of an N-heterocyclic ring, or pharmaceutical compositions comprising them. The patient could be expected to be warned of some or all of the effects of the disease or disorder, or could significantly improve his condition or recovery with respect to patients who were not previously treated. Having thus described the invention, it will be apparent that it can be varied in many ways. Such variations should not be considered to depart from the scope and scope of the invention and it is intended that all such modifications be included within the scope of the following claims.

Claims (36)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound having the formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain C1-C9 alkyl, straight or branched chain C2-C9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or a straight or branched chain C, C, C2-C alkenyl or C2-C2 alkynyl; R2 is a carboxylic acid or a carboxylic acid ester; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents that are selected from R3 and Z, wherein R3 and Z are independently hydrogen , hydroxy, halogen, halogenoalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain C -? - C6 alkyl, straight or branched chain C2-C6 alkenyl or alkynyl, aryl, aralkyl, heteroaryl, carbocyclic, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain C-? -C9 alkyl or C2-C9 alkenyl straight or branched chain; or a pharmaceutically acceptable salt, ester, or solvate thereof; with the proviso that: when n = 1, and D is a bond, and R is COOH, then Ri is not straight or branched chain C? -C9 alkyl, straight or branched chain C2-Cg alkenyl, cycloalkyl C5-C7, C5-C7 cycloalkenyl, phenylamine, 2- (3,4-dichlorophenyl) ethyl, hydroxy, ethoxy, benzyl, or Ar-i, wherein An is 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 1-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, and wherein said alkyl, alkenyl, Cycloalkyl, cycloalkenyl or Ari are optionally substituted with one or more substituents that are selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, straight or branched chain C-C9 alkyl, straight-chain C2-Cg alkenyl or branched, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, COOH, and amino; with the proviso further that: when n = 1, and D is a bond, and R2 is the carboxylic acid isostere -CONZ (R3), and Z is hydrogen or C-C-alkyl, and R3 is phenol, or alkyl or straight or branched chain C2-C3 alkenyl, wherein said alkyl is unsubstituted or substituted at one or more positions with Ar2 as defined below, C3-C8 cycloalkyl, cycloalkyl connected by methyl or an alkyl or alkenyl chain of straight or branched chain C2-Cβ, C? -C4 alkyl ester, or Ar3 wherein Ar3 is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl , 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, having 1 to 3 substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl , straight or branched C? -C6 alkyl, straight or branched C2-C6 alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy and amino; wherein said alkyl ester is optionally substituted with phenyl; or R3 is the fragment: wherein R4 is selected from the group consisting of straight or branched chain Ci-Cg alkyl optionally substituted with C3-C9 cycloalkyl, benzyl, or Ar2 as defined below, and wherein R2 is COOZ or CONR6, wherein R6 is selected from the group consisting of hydrogen, straight or branched Ci-Cβ alkyl and straight or branched C2-CT alkenyl, and wherein R5 is selected from the group consisting of phenol, benzyl, straight Ci-Cß alkyl or branched and straight or branched C2-C6 alkenyl, wherein said alkyl or alkenyl is optionally substituted with phenyl; then R1 is not straight or branched chain C-i-Cg alkyl, straight or branched chain C2-C9 alkenyl, substituted thiophene, or C1-C4 alkoxy, wherein said alkyl or alkenyl is optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, or Ar2, wherein Ar2 is defined later, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl or hydroxy, and wherein Ar 2 is 1-naphthyl, 2-naphthyl, 2-indoyl, 3-indolyl, -furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, having 1 to 3 substituents selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, straight branched Ci-Cß alkyl, straight branched C 2 -C 2 alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy and amino; with the proviso further that: when n = 1, and X is O, and D is a bond, and R2 is -CONH2, then R1 is not methyl, ethyl, isopropyl, isobutyl, stilpentyl, 4-methylpentyl, indolyl, phenyl or hydroxy phenyl; with the proviso also that: when n = 1, and X is O, and D is a bond, and R2 is cyano, then R1 is not methyl; with the proviso also that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3), and R1 is ethoxy, then R3 or Z is not phenyl substituted with halogen; with the proviso that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3) and R1 is thiophene or tetrahydropyranoxy, or substituted methoxy, then R3 or Z is not ethyl substituted with C 1 -C 4 alkyl ester; with the proviso that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3) and R1 is ethoxy, then R3 or Z is not 4-chlorophenyl; with the proviso further that: when n = 2, and X is O, and D is a bond, and R2 is CONZ (R3) and R1 is cyclohexyl, then R3 or Z is not ethyl or propyl substituted with phenyl; with the proviso further that: when D is CH2, then R2 is not -OMe, -NHMe, or -NHcyclichexyl substituted; with the proviso further that: when D is CH2, and R2 is -OH, then Ri is not phenyl or pyrrolidinemethanol; with the proviso that: when n = 2, and X is O, and D is a bond, and R2 is COOH, then Ri is not methyl, tert-butyl, 1,1-dimethyl-2-methyl-propi lo, 1,1-dimethyl-propyl, methoxy, ethoxy, phenyl, C 1 -C 4 alkyl substituted with tetrahydropyranoxy, 1-methyl-1-methoxyamide, 1-methylcyclohexyl, 3-iodophenyl, 3-methyl-cyclopentyl ester, 1, 1-dimethyl-6-phenyl-hex-3,5-dioxy, or trimethoxyphenyl.

2. The compound according to claim 1, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure ring is optionally substituted with R3 in one or more positions.

3. The compound according to claim 1, further characterized in that R2 is selected from the group consisting of: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions.

4. The compound according to claim 1, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2) -CON (R3) 2, - CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN.

5. The compounds (2S) -1- (1> 2-d-oxo-3,3-d-methylpentyl) -2-hydroxymethylpyrrolidine; (2S) -1 - (1, 2-dioxo-3,3-dimethylpentyl) -2-pyrrolidintetrazole; (2S) -1- (1,2-dioxo-3,3-dimethyltyl) -2-pyrrolidylcarbonitrile; and (2S) -1- (1, 2-dioxo-3,3-d-methylpentyl) -2-aminocarbonylpiperidine; and the compounds 1-25, 27, 28, 31-33, and 35-136 of Tables I, II, and III.

6. A pharmaceutical composition comprising: a) an effective amount of a carboxylic acid or an isostere of N-heteroclic carboxylic acid; and b) a pharmaceutically acceptable vehicle.

7. The pharmaceutical composition according to claim 6, further characterized in that the carboxylic acid or the isostere of N-hetercyclic carboxylic acid comprises a compound of the formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain C ^ Cg alkyl or alkenyl, straight or branched chain C 2 -Cg alkenyl, aryl, heteroaryl, carbocyclo or heterocycle; D is a bond, or a straight or branched chain C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 0 alkynyl; R2 is a carboxylic acid or a carboxylic acid isostere; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic or heterocyclic is optionally substituted with one or more substituents that are selected from R3, wherein R3 is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy alkylates ryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain Ci-Cs alkyl, straight or branched chain alkenyl or C2-C6 alkynyl, aryl, aralkyl, heteroaryl, carbocyclo, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain Ci-Cg alkyl or straight or branched chain C2-Cg alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof.

8. The pharmaceutical composition according to claim 7, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said Annular structure is optionally substituted with R3 in one or more positions.

9. The pharmaceutical composition according to claim 7, further characterized in that R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions.

10. The pharmaceutical composition according to claim 7, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2 , -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN.

11. The pharmaceutical composition according to claim 7, further characterized in that the N-heterocyclic carboxylic acid or carboxylic acid compound is selected from the group consisting of compounds 1-139.

12. The pharmaceutical composition according to claim 6, further characterized in that it also comprises a neurotrophic factor different from that of the formula (I).

13. - The pharmaceutical composition according to claim 12, further characterized in that said neurotrophic factor different from that of the formula (I) is selected from neurotrophic growth factor, growth factor obtained from brain, growth factor obtained from the glia, ciliary neurotrophic factor, nsulinic growth factor, and truncated active derivatives thereof, fibroblast acid growth factor, fibroblast basic growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5.

14. A method for treating a neurological disorder in an animal, comprising: administering to said animal an effective amount of a carboxylic acid or steroid of N-heterocyclic carboxylic acid to stimulate the growth of damaged peripheral nerves or to promote regeneration of neurons.

15. The method according to claim 14, further characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathies caused by physical damage or disease status, physical damage to the brain, physical damage to the spinal cord, associated embolism with damage to the brain and neurological disorders related to neuronal degeneration.

16. The method according to claim 14, further characterized in that the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

17. - The method according to claim 14, further characterized in that the neurological disorder is Alzheimer's disease.

18. The method according to claim 14, further characterized in that the neurological disorder is Parkinson's disease.

19. The method according to claim 14, further characterized in that the neurological disorder is amyotrophic lateral sclerosis.

20. The method according to claim 14, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid is not immunosuppressant.

21. The method according to claim 14, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid comprises a compound of the formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain CrC9 alkyl or alkenyl, straight or branched chain C2-C9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or straight or branched chain C1-C10 alkyl, C2-C3 alkenyl or C2-C alkynyl 0; R2 is a carboxylic acid or a carboxylic acid isostere; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents selected from R3, where R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy , alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, alkyl CI-CT straight or branched chain alkyl or C2-CT straight or branched chain, aryl , aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 where R7 is hydrogen or alkyl of C Cg straight or branched chain C2-Cg straight or branched chain; or a pharmaceutically acceptable salt, ester or solvate thereof.

22. The method according to claim 21, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure ring is optionally substituted with R3 in one or more positions.

23. The method according to claim 21, further characterized in that R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions.

24. The method according to claim 21, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2) -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN.

25. The method according to claim 14, further characterized in that the carboxylic acid or NOS heterocyclic carboxylic acid compound is selected from the group consisting of compounds 1-139.

26. The method according to claim 14, further characterized in that it also comprises administering a neurotrophic factor different from that of the formula (I).

27. The method according to claim 26, further characterized in that said neurotrophic factor different from that of the formula (!) Is selected from neurotrophic growth factor, growth factor obtained from brain, growth factor obtained from the glia, factor ciliary neurotrophic insulin growth factor and active truncated derivatives thereof, acidic factor, fibroblast growth factor, basic fibroblast growth, growth factors obtained from platelets, neurotrophin-3 and neurotrophin 4/5.

28. A method for stimulating growth damaged peripheral nerves, comprising: administering to damaged peripheral nerves an effective amount of a carboxylic acid or carboxylic acid isostere N-heterocyclic to stimulate or promote growth of the damaged peripheral nerves.

29. - The method according to claim 28, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid is not immunosuppressant.

30. The method according to claim 28, further characterized in that the carboxylic acid or isostere of carboxylic acid N-heterocyclic comprises a compound of the formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain Ci-Cg alkyl or alkenyl, straight or branched chain C2-C9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or straight or branched chain C? -C10 alkyl, C2-C? 0 alkenyl or C2-C? Alkynyl; R2 is a carboxylic acid or a carboxylic acid isostere; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents that are selected from R3, wherein R3 is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy , alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain Ci-Cs alkyl, straight or branched chain C2-C6 alkenyl or alkynyl, aryl , aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain C-i-Cg alkyl or straight or branched chain C2-Cg alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof.

31. The method according to claim 30, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure ring is optionally substituted with R3 in one or more positions.

32. The method according to claim 30, further characterized in that R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions.

33. The method according to claim 30, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN.

34. The method according to claim 28, further characterized in that the carboxylic acid or isostere compound of N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-139.

35. The method according to claim 28, further characterized in that it also comprises administering a neurotrophic factor different from that of formula (I).

36. - The method according to claim 35, further characterized in that said neurotrophic factor different from that of the formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor obtained from brain, growth factor obtained from the glia , ciliary neurotrophic factor, nsulinic growth factor, and truncated active derivatives thereof, fibroblast acid growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5. 37.- A method for promoting the regeneration and growth of neurons in animals, comprising: administering to an animal an effective amount of a carboxylic acid or isostere of N-heterocyclic carboxylic acid to promote the regeneration of neurons. 38. The method according to claim 37, further characterized in that the carboxylic acid or isosteroid of carboxylic acid N-heterocyclic is not immunosuppressant. 39.- The method according to claim 37, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid comprises a compound of the formula (I): in which n is 1-3; X can be O or S; R t is selected from the group consisting of straight or branched chain C 1 Cg alkyl or alkenyl, straight or branched chain C 2 -C alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or a straight or branched chain C1-C10 alkyl, C2-C10 alkenyl or C2-C-? Alkynyl; R2 is a carboxylic acid or a carboxylic acid ester; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents that are selected from R3, wherein R3 is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain C6 alkyl, straight or branched chain alkenyl or C2-C6 alkynyl, aryl, aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain Ci-Cg alkyl or straight or branched chain C2-Cg alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof. 40. The method according to claim 39, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure ring is optionally substituted with R3 in one or more positions. 41.- The method according to claim 39, further characterized in that R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions. 42. The method according to claim 39, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2 > -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2) -CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN. 43. The method according to claim 37, further characterized in that the carboxylic acid or isostere compound of N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-139. 44. The method according to claim 37, further characterized in that it also comprises administering a neurotrophic factor different from that of the formula (I). 45. The method according to claim 44, further characterized in that said neurotrophic factor different from that of formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor obtained from brain, growth factor obtained from glia, ciliary neurotrophic factor, insulin growth factor, and truncated active derivatives thereof, fibroblast acid growth factor, fibroblast basic growth factor, platelet growth factors, neurotropin-3 and neurotropin 4/5. 46. A method for preventing neurodegeneration in an animal, comprising: administering to an animal an effective amount of a carboxylic acid or steroid of N-heterocyclic carboxylic acid to prevent neurodegeneration. 47. The method according to claim 46, further characterized in that the neurodegeneration is Alzheimer's disease. 48. The method according to claim 46, further characterized because the neurodegeneration is Parkinson's disease. 49. The method according to claim 46, further characterized in that the neurodegeneration is amyotrophic lateral sclerosis. 50. The method according to claim 46, further characterized in that the carboxylic acid or isostere of carboxylic acid N-heterocyclic is not immunosuppressant. 51. The method according to claim 46, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid comprises a compound of the formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain Cg alkyl or alkenyl, straight or branched chain C2-C9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or a straight or branched chain C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R2 is a carboxylic acid or a carboxylic acid ester; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents that are selected from R3, wherein R3 is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy , alkyloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain Ci-Cß alkyl, straight or branched chain C2-C6 alkenyl or alkynyl, aryl , aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain Ci-Cg alkyl or straight or branched chain C2-Cg alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof. 52. The method according to claim 51, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure ring is optionally substituted with R3 in one or more positions. 53. The method according to claim 51, further characterized in that R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions. 54. The method according to claim 51, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN. The method according to claim 46, further characterized in that the carboxylic acid or isostere compound of N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-139. 56. The method according to claim 46, further characterized in that it also comprises administering a neurotrophic factor different from that of the formula (I). 57. The method according to claim 56, further characterized in that said neurotrophic factor different from that of formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor obtained from brain, growth factor obtained from glia, ciliary neurotrophic factor, nsulinic growth factor and truncated active derivatives thereof, fibroblast acid growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5. 58.- A method for treating alopecia or for promoting hair growth in an animal, which comprises administering to said animal an effective amount of a carboxylic acid or isostere of N-heterocyclic carboxylic acid. 59. The method according to claim 58, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid is not immunosuppressant. The method according to claim 58, further characterized in that the carboxylic acid or isostere of N-heterocyclic carboxylic acid is a compound of the formula (I): in which n is 1-3; X can be O or S; R-i is selected from the group consisting of straight or branched chain C-? -C9 alkyl or alkenyl, straight or branched chain C2-Cg alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or a straight or branched chain C-I-C-IO alkyl, C2-C? 0 alkenyl or C2-C-? Alkynyl; R2 is a carboxylic acid or a carboxylic acid ester; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or isoster of carboxylic acid is optionally substituted with one or more substituents that are selected from R3, wherein R3 is hydrogen, hydroxy, halogen, haloalkyl , thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, methyl, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain C-? - C6 alkyl, alkenyl or C2 alkynyl -C6 straight or branched chain, aryl, aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain C-pCg alkyl or straight or branched chain C2-Cg alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof. 61.- The method according to claim 60, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure annular is optionally substituted with R3 in one or more positions. 62. The method according to claim 60, further characterized in that R2 is selected from the following group: wherein the atoms of said ring structure can be optionally substituted with R3 in one or more positions. 63.- The method according to claim 60, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN. 64. The method according to claim 58, further characterized in that the carboxylic acid or isostere compound of N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-139. 65.- A pharmaceutical composition comprising: (i) an effective amount of a carboxylic acid or an isostere of N-heterocyclic carboxylic acid to treat alopecia or to promote hair growth in an animal; and (i) a pharmaceutically acceptable carrier. 66.- The pharmaceutical composition according to claim 65, further characterized in that the carboxylic acid or isosteroid of N-heterocyclic carboxylic acid is not immunosuppressant. 67. The composition according to claim 65, further characterized in that the carboxylic acid or carboxylic acid acid is a compound of the formula (I): in which n is 1-3; X can be O or S; Ri is selected from the group consisting of straight or branched chain C-i-Cg alkyl or alkenyl, straight or branched chain C2-C9 alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond, or a straight or branched chain C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 0 alkynyl; R2 is a carboxylic acid or a carboxylic acid ester; and wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or isosteroid of carboxylic acid is optionally substituted with one or more substituents that are selected from R3, wherein R3 is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, methyl, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain Ci-Cß alkyl, alkenyl or C2-Cß alkynyl straight or branched chain, aryl, aralkyl, heteroaryl, carbocycle, heterocycle, and CO2R7 in which R7 is hydrogen or straight or branched chain Ci-Cg alkyl or straight or branched chain C2-C9 alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof. 68.- The composition according to claim 67, further characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in a chemically stable oxidation state, wherein any of the atoms of said structure ring is optionally substituted with R3 in one or more positions. 69.- The composition according to claim 67, further characterized in that R2 is selected from the following group: wherein the atoms of said annular structure may be, optionally substituted with R3 at one or more positions. The composition according to claim 67, further characterized in that R2 is selected from the group consisting of: -COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (O) R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN. 71. The composition according to claim 65, further characterized in that the carboxylic acid or isostere compound of N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-139.