MXPA00011808A

MXPA00011808A - N-linked sulfonamides of n-heterocyclic carboxylic acids or carboxylic acid isosteres

Info

Publication number: MXPA00011808A
Application number: MXPA/A/2000/011808A
Authority: MX
Inventors: Mark H Norman; S Hamilton Gregory; Yongqian Wu
Original assignee: Amgen Inc*; Gpi Nil Holdings Inc
Priority date: 1998-06-03
Filing date: 2000-11-29
Publication date: 2002-07-25

Abstract

This invention relates to novel N-linked sulfonamides of N-heterocyclic carboxylic acid and carboxylic acid isosteres, their preparation, and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, and for treating alopecia and promoting hair growth.

Description

NON-LINKED NON-LINKED CARBOXYLIC ACIDS N-HETEROCICLICOS OR ISOSTEROS DE CARBOXILICO ACIDO BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to small molecule compounds and compositions, their preparation and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, and for treating alopecia and promoting hair growth. 2. Description of the Previous Technique It has been found that picomolar concentrations of an immunosuppressant, such as FK506 and rapamycin, stimulate neurite outgrowth in PC12 cells and sensory nerve cells, ie dorsal root ganglion cells (DRGs). Lyons et al., Proc. of Nati. Acad. Sci. , 1994 vol. 91, pp. 3191-3195. In complete animal experiments, FK506 has been shown to stimulate nerve regeneration after facial nerve damage and results in functional recovery in animals with sciatic nerve injuries.

Ref. 0125291 Several neurotrophic factors that produce specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer's disease results from a decrease or loss of nerve growth factor (NGF). That is why it has been proposed to treat Alzheimer's patients with exogenous nerve growth factor and other neurotrophic proteins, such as brain-derived growth factor (BDNF), glial-derived nerve factor, ciliary neurotrophic factor, and neurotropin-3 to increase the survival of degenerated neuronal populations.

The clinical application of these proteins in several neurological disease states is hampered by the difficulties in the delivery and bioavailability of large proteins to the nervous system targets. In contrast, immunosuppressive drugs with neurotrophic activity are relatively small and show excellent bioavailability and specificity. However, when administered chronically, immunosuppressants show a number of potentially serious side effects including nephrotoxicity, such as impairment of 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 which are useful for neurotrophic effects and for treating neurodegenerative disorders.

Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systemic disorders, such as eating disorders and internal secretion disorders. The mechanisms that cause hair loss are very complicated, but in certain cases they can be attributed to aging, genetic constitution, the activation of male hormones, the loss of blood supply to the hair follicles, and abnormalities of the scalp.

The immunosuppressive drugs FK506, rapamycin and cyclosporin are well known as specific immunosuppressants of potent T cells, 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. Dermatol, Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner. A form of hair loss, alopecia areata, is known to be associated with autoimmune activities; therefore, immunomodulatory compounds administered topically are expected to show efficacy in treating that type of hair loss. The effects that stimulate hair growth of the FK506 have been the subject of an international patent presentation covering the FK506 and related structures thereto for the stimulation of hair growth (Honbo et al., EP 0 423 714 A2). Honbo et al. describes the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.

The effects of growth and revitalization of hair FK506 and related agents are described in many United States patents (Goulet et al., U.S. Pat.

No. 5,258,389; Luly et al., United States Patent No. ,457,111; Goulet et al., United States Patent No. ,532,248; Goulet et al., United States Patent No. ,189,042; and Ok et al., U.S. Patent No. 5,208,241; Rupprecht et al., U.S. Patent No. 5,284,840; Organ et al., U.S. Patent No. 5,284,877). These patents claim the compounds related to FK506. Although they do not claim hair revitalization methods, they describe the known use of FK506 to effect hair growth. Similar to FK506 (and the variations claimed in the Honbo et al. Patent), the compounds claimed in these patents are relatively large. In addition, the patents cited refer to immunomodulatory compounds for use in related autoimmune diseases, for which the efficacy of FK506 is well known.

Other US patents describe the use of cyclosporin 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. Pat. United No. 4,996,193). These patents also refer to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth.

However, immunosuppressive compounds by definition suppress the immune system and also show other toxic side effects. Accordingly, there is a need for small molecule compounds, which are useful as hair revitalization compounds.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the surprising discovery that N-heterocyclic sulfonamide compounds containing a carboxylic acid or carboxylic acid portion can be useful for treating neurodegenerative disorders and for treating alopecia and promoting hair growth. Accordingly, a new class of sulfonamide derivatives containing an acid part or an isostere thereof bound to carbon 2 of the N-heterocyclic ring is provided. These compounds stimulate neuronal regeneration and outgrowth and as such are useful for treating neurological disorders and neurodegenerative diseases. 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 having the formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl Ci-Cg, straight or branched chain alkenyl C2-C9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl C? -C10, C2.-C? 0 alkenyl or C-C10 alkynyl; R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or isomer of C-carboxylic acid 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, straight or branched chain alkyl Cx-Ce, straight or branched C2-C6 alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or straight or branched chain alkyl or alkenyl Cx-Cg; or a pharmaceutically acceptable salt, ester or solvate thereof; with the condition that: when D is a bond, and R2 is COOH, then Ri can not be substituted naphthyl; also with the condition that: when D is a bond, and n is 1, and R2 is COOH or CONHR3, then Ri is not hydroxy, methyl, ethyl, substituted or unsubstituted thioethyl, benzothiazole, substituted benzopyran, substituted benzopyrrole, substituted benzoxazole, substituted 5-membered heterocycle it contains two heteroatoms of N and one heteroatom of S, or phenyl, phenylethyl, naphthyl, pyridyl, thienyl, quinoline, tricyclic ring, aminoethyl, or substituted or unsubstituted benzyl; -Also with the condition that: when D is a bond, and n is 2, and R2 is COOH or phenylbutyl ester, then Ri is not substituted phenyl, or a substituted bicyclic ring containing two oxygen heteroatoms; also with the condition that: when D is a bond, and n is 1-2, and R2 is a substituted or unsubstituted carbocyclic or heterocyclic ring structure, then Rx is not substituted or unsubstituted carbocycle or heterocycle, or hydroxy; also with the condition that: when D is a bond, and n is 1-2, and R2 is hydroxy, alkoxy, -S02 (phenyl), N (R3) 2, uncle or substituted alkylthio, -NCO, -P03 (Me) 2, or -NCOOC ( ethyl) phenyl, then R1 # is not naphthalene, ethylene, substituted tricyclic ring, or substituted or unsubstituted phenyl; also with the condition that: when D is C? -C3 alkyl or hexenyl, and R2 is hydroxyl, then Rx is not substituted or unsubstituted phenyl, or benzoimidazole; -Also with the condition that: when D is methyl, and n is 1, and R2 is cyano or COOH, then Rx is not substituted phenyl; also with the condition that: when D is methyl, and n is 1, and R2 is methoxy or N (R3) 2, then Rx is not methyl, ethyl, phenylethyl, substituted chloro-alkyl, substituted oxirane, substituted aziridine wherein one of the carbons is replaced with a oxygen, substituted or unsubstituted propenyl, substituted phenyl, benzyl, or trifluoro-alkyl or C2-C3 alkenyl; also with the condition that: when D is ethyl, and n is 2, and R2 is hydroxyl or N (R3) 2, then Ri is not naphthyl; also with the condition that: when D is propyl, and n is 1, and R2 is methoxy, then Rj. it is not ethylene, substituted cyano-ethyl, or substituted triethoxy-propyl; -Also with the condition that: when D is not a bond and at least one of D and R2 contains at least one atom of S or 0, then Ri is not methyl or substituted phenyl.

A preferred embodiment of this invention is where R 2 is a carbocycle or heterocycle containing any combination of CH 2, 0, S, or N in any chemically stable oxidation state, wherein any of the atoms of the ring structure are optionally substituted in a or more positions with R3.

The preferred embodiments especially of this invention are where R2 is selected from the group below: where the atoms of the ring structure can optionally be substituted in one or more positions with R3.

Another preferred embodiment of this invention is where R2 is selected from the group consisting of -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3 , -N (R3) 2, -C0N (R3) 2, -CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN.

Preferred embodiments of this invention are the compounds of the formula: (2S) -1- (phenylmethyl) sulfonyl-2-hydroxymethylpyrrolidine; (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidintetrazole; (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidinecarbonitrile; and compounds 1-136.

Another preferred embodiment of this invention is a composition containing: a therapeutically effective amount of a compound of formula (I); a neurotrophic factor different from formula (I); and a pharmaceutically suitable carrier.

Another preferred embodiment of the invention is a method for promoting regeneration and neuronal growth in mammals, which comprises administering to a mammal an effective amount of an N-linked sulfonamide of a carboxylic acid.

N-heterocyclic or carboxylic acid isostere.

Another preferred embodiment of the invention is a method for treating a neurological disorder in an animal, comprising administering to an animal a therapeutically effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere to stimulate growth. of damaged peripheral nerves or promote neuronal regeneration.

Yet another preferred embodiment of the invention is a method for preventing neurodegeneration in an animal, comprising administering to an animal an effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere.

Yet 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 an N-linked sulfonamide of an N-heterocyclic carboxylic acid or acid isosteroid. carboxylic 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 six weeks. Figure 2 shows that less than 3% of the shaved 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 N-heterocyclic carboxylic acids or carboxylic acid isosteres at 1 μmol per milliliter three times per week.

Hair growth was evaluated after 14 days of treatment.

DETAILED DESCRIPTION OF THE INVENTION Definitions The term "alkyl" means a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms. For example, the linear or branched C 1 -C 5 alkyl hydrocarbon chain contains 1 to 6 carbon atoms, and includes but is not limited to substituents, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl , tert-butyl, n-pentyl, n-hexyl, and the like. It is also contemplated within the scope of the present invention that the term "alkyl" may also refer to a hydrocarbon chain wherein any of the alkyl carbon atoms is optionally replaced with O, NH, S, or S02. For example, carbon 2 of n-pentyl can be replaced with 0 to form propyloxymethyl.

The term "alkenyl" means a branched or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms. For example, the straight or branched C2-C6 alkenyl hydrocarbon 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, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like. It is also contemplated within the scope of the present invention that the term "alkenyl" may also; refer to an unsaturated hydrocarbon chain, wherein any of the alkenyl carbon atoms are optionally replaced with 0, NH, S, or S02. For example, carbon 2 of 4-pentene can be replaced with O to form (2-propene) oxymethyl.

The term "alkoxy" means the group -OR, wherein R is alkyl as defined herein. Preferably, R is a branched or unimproved saturated hydrocarbon chain containing 1 to 6 carbon atoms.

The term "carbocycle" refers to an organic cyclic part in which the cyclic skeleton is composed of only carbon atoms, while the term "heterocycle" refers to an organic cyclic part in which the cyclic skeleton contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur and which may or may not contain carbon atoms.

In this way, the term "carbocycle" refers to a carbocyclic part containing the indicated number of carbon atoms. The term "C3-C8 cycloalkyl", therefore, refers to an organic cyclic substituent in which three to eight carbon atoms form a ring of three, four, five, six, seven, or eight members, including, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring. As used herein, the term "carbocycle" can also refer to two or more cyclic ring systems, in which they are fused to form, for example, bicyclic, tricyclic, or other similar bridge substituents (eg, adamantyl).

The term "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 different substituents as defined previously. Substituents attached to a portion of the phenyl ring of an aryl portion in the compounds of Formula (I) can be configured in the ortho, meta, or para orientations.

Examples of the typical aryl portions included in the scope of the present invention may include, but are not limited to, the following: The term "aralkyl" refers to an alkyl or alkylene (alkenyl) chain, which is substituted with aryl, heteroaryl, carbocycle or heterocycle, or alternatively one or more aryl, heteroaryl, carbocycle, or heterocycle (s), which they are / are substituted with alkyl or alkenyl, ie, 'Alkyl / alkylene which is substituted with Ar' or 'Ar which is substituted with alkyl / alkylene'.

The term "heterocycle" refers to? a saturated, unsaturated, or aromatic carbocyclic group having a single ring, multiple rings, or multiple fused rings, and having at least one heteroatom, such as nitrogen, oxygen, or sulfur within at least one of the rings. The term "heteroaryl" refers to a heterocycle, in which at least one ring is aromatic. Any of the heterocyclic groups or heteroaryl groups may be unsubstituted or optionally substituted with one or more groups as defined above. In addition, the bi or tricyclic heteroaryl moieties may comprise at least one ring, which is either fully or partially saturated.

As one of ordinary skill in the art will appreciate, such heterocyclic portions may exist in various isomeric forms, all of which are included by the present invention. For example, a part of 1,3,5-triazine is isomeric to a 1,2,4-triazine group. Such positional isomers are considered within the scope of the present invention. In addition, heterocyclic groups or heteroaryl groups can be attached to other parts in the compounds of the present invention. The point (s) of attachment to these other parts is not constructed as limiting in the scope of the invention. Thus, by way of example, a part of pyridyl can be attached to other groups through the 2, 3 or 4 position of the pyridyl group. All similar configurations are discussed within the scope of the present invention.

Examples of the heterocyclic portions or heteroaryl moieties included within the scope of the present invention may include, but are not limited to, the following: The term "halo" means at least a part of fluoro, chloro, bromo or iodo.

The term "pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester, or solvate of the subject compounds, which possess the desired pharmacological activity and which are not biologically or 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, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate. , fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydrochloride, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Basic salt, ester or solvates include ammonium salts, alkali metal salts, such as lithium, sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salt with organic bases, such as salts of dicyclohexylamine , N-methyl-D-glucamine, and salts with amino acids, such as arginine, lysine, and so on. Also, basic nitrogen containing groups can be quaternized with such agents as: 1) lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; 2) dialkyl sulfates similar to 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) aryl or arylalkyl halides similar to benzyl bromide and phenethyl bromide and others.

The compounds of this invention can have at least one asymmetric center and can thus be produced as mixtures of stereoisomers or as individual enantiomers or diastomers. Individual stereoisomers can be obtained by using an optically active starting material, separating a racemic or non-racemic mixture from an intermediate product at some appropriate stage of synthesis, or by separating the compound of formula (I). It is understood that individual stereoisomers, as well as mixtures (racemic and non-racemic) of stereoisomers are included within the scope of the present invention. The stereoisomer S at atom 1 of formula I is a more preferred embodiment of the invention.

"Stereoisomers" are isomers that differ only in the way that atoms are distributed in space.

The "isomers" are different compounds that have the same molecular formula and include cyclic isomers, such as (iso) indole and other isomeric forms of cyclic parts.

The "enantiomers" are a pair of stereoisomers that are mirror images not overlapping each other.

The "diastereoisomers" are stereoisomers which are not mirror images of each other.

The term "racemic mixture" means a mixture containing equal parts of individual enantiomers. The "non-racemic mixture" is a mixture containing unequal portions of individual enantiomers or stereoisomers.

The "isosterers" are different compounds that have different molecular formula but show the same or similar properties. For example, tetrazole is a carboxylic acid isostere because it simulates the properties of the carboxylic acid, even though both have a very different molecular formula. Tetrazole is one of the many possible isosteric replacements for the carboxylic acid. Other carboxylic acid isosteres contemplated by the present invention include -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3 ) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHS02R3, -COHNS02R3, and -C0N 3CN.

In addition, the carboxylic acid isosteres may include carbocycles or 5-7 membered heterocycles containing any combination of CH2, 0, S, or N in any chemically stable oxidation state, where any of the atoms of the ring structure is substituted optionally in one or more positions. The following structures are non-limiting examples of the preferred carbocyclic and heterocyclic isosteres contemplated by this invention. where the atoms of the ring structure can optionally be substituted in one or more positions with R3. The present invention contemplates that when chemical substituents are added to a carbocyclic isostere then the inventive compound retains the properties of a carboxylic isostere. The present invention contemplates that when a carboxylic isostere is optionally substituted with one or more selected parts of R3, then the substitution can not eliminate the isosteric properties of the carboxylic acid of the inventive compound. The present invention contemplates that the placement of one or more substituents R3 on a carbocyclic or heterocyclic carboxylic acid isostere should not be on an atom (s) which maintains or is integral to the isosteric properties of the carboxylic acid of the inventive compound if such a substituent (s) must destroy the isosteric properties of the carboxylic acid of the inventive compound.

Other carboxylic acid isosteres not exemplified or specifically described in this specification are also contemplated by the present invention.

The term "prevention of neurodegeneration" as used herein includes the ability to inhibit or prevent neurodegeneration in newly diagnosed patients who have a neurodegenerative disease, or at risk of developing a new degenerative disease and to further inhibit or prevent neurodegeneration in patients. who already suffer from or have symptoms of a neurodegenerative disease when the compounds occur concurrently.

The term "treatment" as used herein 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 an individual, who may be predisposed to the disease and / or condition, but who has not yet been diagnosed as having it; (ii) inhibit the disease and / or condition, that is, stop its development; or (iii) alleviating the disease and / or condition, that is, 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 formula I as an example.

A compound of the present invention, especially of formula (I), wherein n is 1, D is a bond, Ri is phenylmethyl, and R2 is -CN, is (2S) -1- (phenylmethyl) sulfonyl-2 - pyrrolidinecarbonitrile.

The term "alopecia" refers to the growth of deficient hair and partial or complete hair loss, which includes without limitation the androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, peeled alopecia and trichotillomania. Alopecia results when the hair cycle is altered. The most frequent phenomenon is a shortening of hair growth or anagen phase due to the cessation of cell proliferation. This results in an early attack of the catagen phase, and therefore a large number of hairs in the telogen phase during which the follicles are separated from the dermal papilla, and the hair falls out. Alopecia has a number of etiologies, which include genetic factors, aging, local and systemic diseases, febrile conditions, mental tensions, hormonal problems, and side effects of drugs.

The term "hair cycle" refers to the life cycle of the hair follicles, and includes three phases: (1) the anagen phase, the period of growth of active hair which, as far as the hair of the scalp is concerned, lasts approximately three to five years .. (2) the catagen phase, the period when the growth stops and the follicle atrophies which, as far as the hair of the scalp is concerned, lasts approximately one to two weeks; Y (3) the telogen phase, the resting period when the hair separates progressively and finally falls out which, as far as the hair of the scalp is concerned, lasts approximately three to four months.

Normally 80 to 90% of the follicles are in the anagen phase, less than 1 percent is in the catagen phase, and the rest is in the telogen phase. In the telogen phase, the hair is of uniform diameter with a non-pigmented root, slightly bulbous. By contrast, in the anagen phase, the hair has a large colored bulb at its root.

The term "hair growth promotion" refers to maintaining, inducing, stimulating, accelerating, or revitalizing hair germination.

The term "alopecia treatment" refers to: (i) prevent alopecia in an animal, which may be predisposed to alopecia; and / or (ii) inhibiting, retarding or reducing alopecia; I (iii) promote hair growth; I (iv) prolong the anagen phase of the hair cycle; I (v) convert the hair of hair to grow as terminal hair. The terminal hair is thick, pigmented, and long hair in which the bulb of the hair follicle is placed deep in the dermis. Hair hair, on the other hand, is fine, thin, non-pigmented hair, short in which the hair bulb is located superficially in the dermis. Since alopecia continues, the hair changes from the terminal type to the type of hair.

The term "neurotrophic" as used herein includes without limitation the ability to stimulate neuronal growth or regeneration and / or the ability to prevent or treat neurodegeneration.

The term "non-immunosuppressant" refers to the inability of the compounds of the present invention to activate an immune response when compared to a control, such as FK506 or cyclosporin A. Tests to determine immunosuppression are well known to those of ordinary skill in the art. Specific non-limiting examples of well-known assays include assays with PMA and 0KT3, where mitogens are used to stimulate the proliferation of human peripheral blood lymphocytes (PBC). The compounds added to such assay systems are evaluated for their ability to inhibit such proliferation.

Compounds of the Invention The present invention relates to the surprising discovery that the N-linked sulfonamide compounds of N-heterocyclic carboxylic acid or carboxylic acid isostere are neurotrophic and capable of treating alopecia. Accordingly, a new class of compounds is provided. A preferred feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity.

Preferred compounds of the present invention contain carboxylic acid portions and other isoteric replacements for the carboxylic acid portions, of which several examples are specified herein. Other isothermal replacements for the carboxylic acid portions, known to those skilled in the medical chemistry art, are within the scope of the invention if not otherwise specified.

The neurotrophic compounds of this invention can be periodically administered to a patient who is undergoing treatment for neurological disorders or for other reasons, in which it is desirable to stimulate neuronal growth and regeneration, such as in several peripheral neuropathic and neurological disorders that are related to to neurodegeneration. The compounds of this invention can also be administered to mammals other than humans, for the treatment of various mammalian neurological disorders.

The novel compounds of the present invention possess an excellent degree of neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and in the treatment of several known neurological disorders that are associated with neuronal degeneration 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 inherited muscular atrophy, herniated invertebrate disc syndromes , broken or prolapsed, cervical spondylosis, plexus disorders, syndromes of destruction of the thoracic outlet, peripheral neuropathic disorders, such as those caused by lead, dapsone, -garrapatas, profiria, or Guillain-Barré syndrome, Alzheimer's disease, and Parkinson's disease.

The above discussion which relates to 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 herein refers to any carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, flavoring, or sweetener.

For these purposes, the compounds of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via a reservoir implanted in dosage formulations containing carriers, adjuvants and pharmaceutically acceptable non-toxic vehicles. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecally, intraventricularly, intrasternal, 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. Dosage forms in tablet form 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 agents and suspending agents combined with the active ingredient.

When the dosage form is prepared by incorporating the compositions of the invention, the compounds can also be mixed 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 methylparaben, propylparaben, and sodium benzoate; surfactants, such as sodium laurisulfate, polysorbate 80, and the like; dyes, such as colorants F.D. &C .; and lacquers; flavors; and sweeteners.

The compositions and methods of the invention can also use controlled release technology. Thus, for example, the inventive compounds can be incorporated into a hydrophobic polymer matrix for controlled release over a period of days. Such controlled release films are well known to the art. Particularly preferred are transdermal delivery systems. Other examples of polymers commonly employed for this purpose that may be used in the present invention include non-degradable ethylene-vinyl acetate copolymer and degradable lactic acid-glycolic acid copolymers, which may 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 than the other polymer release systems, such as those mentioned above.

To be effective therapeutically as targets of the central nervous system, the compounds of the present invention must readily penetrate the blood brain barrier when administered peripherally. The compounds which can not penetrate the blood brain barrier can be effectively administered by an intraventricular route or other appropriate delivery system suitable for administration to the brain.

The compounds of the present invention can be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing agents or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in parenterally non-toxic 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, fixed, sterile oils such as solvents or suspending media are conventionally employed. For this purpose, any soft fixed oil, including synthetic mono or diglycerides, may be employed. Fatty acids, such as oleic acid and its glyceride derivatives, which include olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectable products. These oil solutions or suspensions may also contain diluents or long-chain alcohol dispersing agents.

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 directed for the treatment comprise easily accessible areas or organs for topical application, including neurological disorders of the eye, the skin, or the lower intestinal tract. Suitable 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 pH-adjusted sterile saline, or, preferably, as solutions in sterile, pH-adjusted, isotonic saline solution, either with or without a preservative, such as benzylalkonium chloride. Alternatively for ophthalmic uses, the compounds may be formulated into an ointment, such as petrolatum.

For topical application to the skin, the compounds can be formulated into a suitable ointment containing the suspended or dissolved compound in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol , composed of polyoxyethylenepolyoxypropylene, emulsifying wax and water. Alternatively, the compounds can 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, cetyl ester wax , cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical application to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.

Dosage levels in the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in 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, the results of the dosage effect in vi tro provide a useful guide on the appropriate doses for administration to the patient. 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 dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, and the severity of the particular disease being treated and form of administration.

To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions 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 can be formulated into 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, polyoxyethylenepolyoxypropylene, emulsifying wax and water. Alternatively, the compounds can be formulated in suitable 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-octyldodecanol, benzyl alcohol and water.

The compounds can be administered for the treatment of hair loss with other hair revitalizing agents. The specific dose levels for the other hair revitalization agents will depend on the previously established factors and the efficacy of the drug combination.

Other routes of administration known in the pharmaceutical art are also contemplated by this invention.

The specific embodiments of the inventive compounds are presented in Table I. The present invention contemplates employing the compounds of Table I, below, 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 promoting growth of hair on an animal, and all the different uses suggested in this specification.

T? BLA_ or. n 83 benzyl link 84 benzyl link 85 benzyl link 86 benzyl link 87 benzyl link 88 benzyl link 89 benzyl link The carboxylic and isosternal acids of additional claimed or comparative N-heterocyclic compounds, which also show the remarkable neurotrophic and hair-growing effects of the present invention are shown below in Table II: TABLE II where Y and Z are carbon for the compounds AK, COOH 1, 2-dioxoethyl 1,1-dimethylpropyl bond, COOH 1, 2-d-oxoethyl 1,1-dimethylpropyl bond where Z is S for compound H or where Y is S for compound I.

Pharmaceutical Compositions of the Present Invention The present invention relates to a composition comprising: (i) an effective amount of an N-linked sulfonamide compound of N-heterocyclic carboxylic acid or carboxylic acid isostere; Y (ii) a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a compound of: N-linked N-heterocyclic carboxylic acid sulfonamide or carboxylic acid isostere for treating neurodegenerative diseases, neurological disorders, and nerve damage, or promoting nerve growth in an animal; Y (ii) a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of an N-linked sulfonamide compound of N-heterocyclic carboxylic acid or carboxylic acid isostere to treat alopecia or promote hair growth in a animal; Y (ii) a pharmaceutically acceptable carrier.

The neurotrophic compounds can be administered with other neurotrophic agents, such as neurotrophic growth factor, brain-derived growth factor, glial-derived growth factor, ciliary neurotrophic factor, insulin-like growth factor and truncated active derivatives thereof, growth factor. fibroblastic acid, basic fibroblast growth factor, platelet-derived growth factor, neurotropin-3 and neurotropin 4/5. The dosage level of other neurotrophic drugs will depend on the previously established factors and the neurotrophic efficacy of the drug combination.

Methods of the Present Invention The present invention relates to the use of any of the compounds seen in Table I and II and other compounds included 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, attack of paralysis associated with brain damage, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The present invention also relates to the use of carboxylic acid and carboxylic acid isostere compounds to treat the neuropathies mentioned above, neurological disorders, and neurological damage.

The present invention also relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to the animal an effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere. . The present invention also relates to using the inventive compounds and compositions in the preparation of a medicament for the treatment of alopecia or promoting hair growth in an animal.

The inventive method is useful particularly to treat 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 systematic disorders, such as eating 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 employed, age, body weight, general health, sex, diet, time of administration, rate of excretion , combination of drugs, and the severity of the particular disease or disorder being treated and form of administration.

Model of Parkinson's Disease Injured with MPTP in mice The MPTP injury of dopaminergic neurons in mice is used as an animal model of Parkinson's disease. White CD1 mice 4 weeks old are dosed i.p. with 30 mg / kg of MPTP for 5 days. The test compounds (4 mg / kg), or vehicle, are administered s.c. together with the MPTP for 5 days, as well as for an additional 5 days after cessation of MPTP treatment. At 18 days after treatment with MPTP, the animals were sacrificed and the stria is carefully examined and perfusion is fixed.

Immunostaining is carried out in sections of the sagittal and coronal 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 is observed compared to non-injured animals. The injured animals receiving the test compounds show a significant recovery of dopaminergic neurons stained with TH. This model represents the quantification for the recovery of positive dopaminergic neurons stained with TH in the striatum of the animals receiving the compounds of the present invention. Table III shows the percent recovery of dopaminergic neurons in the first model (concurrent dosing) in animals receiving compound 1, (2) -l- [(phenylmethyl) sulfonyl] -2-pyrrolidinecarboxylic acid, also related compounds of the present invention.

Table III, below, shows the remarkable neurodegenerative effects of the carboxylic acid or carboxylic acid isostere compounds illustrating the neurotrophic capacity of the carboxylic acid isosteres as a class showing that the injured animals receiving the acid compounds carboxylic or carboxylic acid isostere provide a remarkable recovery of dopaminergic neurons stained with TH.

Table III - Neurodegenerative Model Injured with MPTP % Recovery Compound A 24.4% Compounds B-E ND Compound F 26.7% Compound G ND Compound H 23.2% Compound I 19.6% Compound J 34.1% Compound K 46.5% Compound L 14.0% Compound M ND The percent density of groove innervation was quantified in sections of the brain with an anti-tyrosine hydroxylase immunoglobulin, which is indicative of functional dopaminergic neurons. The density of innervation of stretch marks of 23% for animals pretreated with only one vehicle and orally administered a vehicle during treatment, is indicative of normal non-injured striated tissue. Stretch innervation density is reduced up to 5% for animals pretreated with MPTP and orally administered a vehicle during treatment, and is indicative of the lesion induced by MPTP. Surprisingly, the density of nerve innervation is increased from 8-13% for animals pretreated with MPTP and administered 0.4 mg / kg of the compound orally during treatment, which indicates substantial neuronal regeneration after induction of lesions derived from MPTP.

In Vitro Hair Generation Test with 6 C57 Black Mice To show the hair revitalization properties of ureas and carbamates of N-heterocyclic carboxylic acids or carboxylic acid isosteres, 6 C57 black mice are used. Referring now to Figures 1 and 2 of the drawings, 6 black C57 mice, approximately 7 weeks old, have a shaved area of approximately 2 inches by 2 inches on their bottoms to remove all existing hair. Care was taken not to cut or cause abrasion to the underlying dermal layers. The animals were in the anagen growth phase, as indicated by the pinkish color of the skin. Referring now to Figure 2, four animals per group were treated by topical administration with 20% propylene glycol vehicle (Figure 2), or related compounds dissolved in the vehicle.

The animals were treated with vehicle or carboxylic acids N-heterocyclic or isosteic each 48 hours (a total of 3 applications over the course of 5 days) and allowed to continue hair growth for 6 weeks. Hair growth was quantified by the percent shaved area covered by the growth of new hair during this period of time.

Figure 2 shows that animals treated with vehicle exhibits only a small amount of hair growth in patches or tufts, with less than 3% shaved area covered with new hair growth.

In contrast, Figure 3 shows that animals treated for 2 weeks' with the N-heterocyclic carboxylic acid compounds, ie compound F, compound G, and compound K exhibit dramatic hair growth, covering more than 25% of the shaved area in all animals for two of the compounds.

Figure 3 shows the relative hair growth in 6 C57 black mice shaved 14 days after being treated with N-heterocyclic carboxylic acids or carboxylic acid isosteres. The mice have a shaved region of 2 inches by 2 inches on their butt to remove all hair. Care was taken not to cut or cause abrasion to the underlying dermal layers. Compounds at a concentration of 1 μmol per milliliter were carefully applied to the -rasured area of the mice (5 mice per group) three times per week. Hair growth was evaluated 14 days after the initiation of treatment with the drug. The relative scale for estimating hair growth is as follows: 0 = no growth; 1 = growth start in small tufts; 2 = hair growth that covers up to < 25% shaved area; 3 = hair growth that covers up to > 25% of the shaved area, but less than 50% of the shaved area; 4 = hair growth that covers up > 50% of the shaved area, but less than 75% of the shaved area; = full hair growth of the shaved area.

The following examples are illustrative of the preferred embodiments of the invention and are not construed as limiting the invention to them. All molecular weights of polymer are average molecular weights. All percentages are based on the percent by weight of the final delivery system or formulation prepared unless otherwise indicated and all totals equal 100% by weight.

EXAMPLES The inventive compounds can be prepared by a variety of synthetic sequences using established chemical transformations. An exemplary general path for the present compounds is described in Scheme I, Scheme II, and Scheme III.

SCHEME I 2N LiOH / MeOK SCHEME I I 1) Dimethyl Iformamide / oxalyl chloride 2) Pyridine SCHEME III EXAMPLE 1 Synthesis d = azids (2S) -N- (benzylsulfonyl) -2-pyrrolidinecarboxylic acid (Table I Compound 1) (Table U and Scheme I Compound A) To a cooled solution (0 ° C) of proline methyl ester hydrochloride salt (5.0 g, 30.19 mmoles) in 200 ml of methylene chloride was added triethylamine (35 ml) and benzenesulfonyl chloride (5.75 g, 30.19 mmoles). . The mixture was stirred for one hour at 0 ° C and then washed with 2 x 100 ml of water. The organic phase was dried and concentrated. Chromatography eluting with 50% EtOAc / hexane gave 8.14 g (5%) of the N-sulfonamide methyl ester, which was dissolved in 120 ml of methanol, cooled to 0 ° C, and treated with 40 ml of hydroxide of lithium ÍN. The mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. After the reaction mixture was acidified (pH = 1) with IN HCl, the product was extracted with methylene chloride and dried and concentrated to yield 4.25 g of (2S) -N- (benzylsulfonyl) -2-pyrrolidinecarboxylic acid ( A) as a white solid, XH NMR (CDC13, 400 MHz): d 1.85-1.90 (m, 2H); 2.08 (m, 1H); 2.18 (m, 1H); 3.04 (m, 1H); 3.27 (m, 1H); 4.32-4.35 (m, 2H); 4.45 (m, 1H); 4.45 (m, 2H); 7.36 (m, 3H); 7.48 (m, 2H); 10.98 (br, 1H).

EXAMPLE 2 synthesis d = (2S) -1- (nylmethylsulfonyl) -2-hydroxymethylpyrrolidine (Compound 95) (Scheme III Compound E) To a solution of (S) - (+) - 2-pyrrolidinemethanol (1.01 g, 10 mmol) and triethylamine (1.5 ml, 11 mmol) in 30 ml of methylene chloride was added 1.9 g (10 mmol) of sodium chloride. toluenesulfonyl at 0 ° C with stirring. The reaction was gradually warmed to room temperature and stirred overnight. The mixture was diluted with water, and extracted with 200 ml of methylene chloride. The organic extract was concentrated and further purified by chromatography on silica gel to give 1.5 g of product as a white solid (58.9% yield). X H NMR (CDC13): d 01.71-1.88 (m, 4H); 2.05 (br, 1H, OH); 3.22 (m, 2H); 3.47 (m, 2H); 3.67 (m, 1H); 4.35 (s, 2H); 7.26-7.44 (m, 5H, aromatic).

EXAMPLE 3 Synthesis d = (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidinecarboxamide (Compound 96) (Scheme II Compound B) To a solution of L-prolinamide (2.28 g, 20 mmol) and triethylamine (5.76 ml, 42 mmol) in 40 ml of methylene chloride was added 3.92 g (20 mmol) of a-toluenesulfonyl chloride at 0 ° C with agitation. The reaction was gradually warmed to room temperature and stirred overnight. The mixture was diluted with water, and extracted with 200 ml of methylene chloride. The organic extract was concentrated and further purified by chromatography on silica gel to give 3.0 g of product as a white solid (55.7% yield). X H NMR (CDC13): d 01.89 (m, 3H); 2.25 (m, 1H); 3.40 (m, 1H); 3.50 (m, 1H); 3.96 (m, 1H); 4.35 (s, 2H); 7.39-7.45 (m, 5H, aromatic).

EXAMPLE 4 Synthesis of (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidinecarbonitrile (Compound 97) (Scheme II Compound O.

To a solution of 0.67 ml of DMF (8.7 mmol) in 10 ml of acetonitrile at 0 ° C was added 0.70 ml (8.0 mmol) of oxalyl chloride. A white precipitate formed immediately and was accompanied by gas evolution. When complete, a solution of 2.0 g (7.5 mmol) of (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidinecarboxamide in 5.0 ml of acetonitrile was added. When the mixture became homogeneous, 1.35 ml (16.5 mmoles) of pyridine was added. After 5 minutes, the mixture was diluted with water, and extracted with 200 ml-ethyl acetate. The organic layer was concentrated and further purified by chromatography on silica gel to give 1.5 g of product as a white solid (80% yield). ES NMR (CDC13): d1.092 (m, 2H); 2.01 (m, 1H); 2.11 (m, 1H); 3.45 (m, 2H); 4.35 (s, 2H); 4.65 (m, 1H); 7.26-7.45 (m, 5H, aromatic).

EXAMPLE 5 Synthesis d = (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidintetrazole (Compound 4) (Scheme II Compound D).

A mixture of (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidinecarbonitrile (250 mg, 1 mmol), NaN3 (81 mg, 1.3 mmol) and NH4C1 (70 mg, 1.3 mmol) in 3 mL of DMF was stirred at 130 ° C for 16 hours. The mixture was concentrated and purified by chromatography on silica gel to give 120 mg of product as a white solid (41.1% yield). X H NMR (CDCl 3): d 01.95 (m, 2H); 2.21 (m, 1H); 2.90 (m, 1H); 3.40 (m, 2H); 4.27 (s, 2H); 5.04 (m, 1H); 7.36-7.41 (m, 5H, aromatic); 8.05 (s, 1H, NH).

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

In 95% ethanol was added an N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, α-tocopherol acetate, adducts (40 moles) of ethylene oxide of hardened castor oil, perfume and dye. The resulting mixture was stirred and dissolved, and purified water was added to the mixture to obtain a clear liquid lotion.

Once or twice a day 5 ml of the lotion was applied to a site that has marked baldness or alopecia.

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

In 95% ethanol there is added an N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, hinokitol, adducts (40 moles) of ethylene oxide of hardened castor oil, perfume, and a dye. 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 once up to 4 times per day to a site that has baldness or marked alopecia.

EXAMPLE 8 An emulsion can be prepared from phase A and phase B having the following compositions.

Phase A and phase B were respectively heated and melted and maintained at 80 ° C. Then both phases were mixed and cooled under stirring to normal temperature to obtain an emulsion.

The emulsion can be applied by spraying once up to 4 times per day to a site that has marked baldness or alopecia.

EXAMPLE 9 A cream can be prepared from phase A and phase B having the following compositions.

Phase A is heated and melted, and maintained at 70 ° C. Phase B is added in phase A and the mixture is stirred to obtain an emulsion. Then the emulsion is cooled to obtain a cream.

The cream can be applied once up to 4 times a day to a site that has marked baldness or alopecia.

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

In ethanol, polyoxypropylene butyl ether, propylene glycol, hardened polyoxyethylene castor oil, an N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, and perfume were added. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid.

The liquid can be applied once up to 4 times a day to a site that has baldness or marked alopecia.

EXAMPLE 11 A shampoo comprising the following composition can be prepared In 69.7 g of purified water are added 5.0 g of sodium laurisulfate, 5.0 g of triethanolamine lauryl sulfate, 6.0 g of betaine lauryl dimethyl-aminoacetate. Then a mixture is obtained by adding 5.0 g of an N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 g of perfume were added successively. The resulting mixture is heated and subsequently cooled to obtain a shampoo.

The shampoo can be used on the scalp once or twice a day.

EXAMPLE 12 A patient suffering from alopecia senilis. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 13 A patient suffering from male pattern alopecia. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 14 A patient suffering from alopecia aretata. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 15 A patient suffering from hair loss caused by skin lesions. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 16 A patient suffering from hair loss caused by tumors. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 17 A patient suffering from hair loss caused by a systematic disorder, such as an eating disorder or a disorder of internal secretion. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 18 A patient suffering from hair loss caused by chemotherapy. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 19 A patient suffering from hair loss caused by radiation. An N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylic acid isostere, or a pharmaceutical composition comprising the same, can be administered to the patient. Expected hair growth is expected after treatment.

EXAMPLE 2Q A patient suffering from a neurodegenerative disease. A carboxylic acid or isostere of carboxylic acid of an N-heterocyclic ring or a pharmaceutical composition comprising the same, is administered to the patient. The patient is expected to improve his condition or recover.

EXAMPLE 21 A patient who suffers from a neurological disorder.

A carboxylic acid or isostere of carboxylic acid of an N-heterocyclic ring or pharmaceutical compositions comprising the same, is administered to the patient. The patient is expected to improve his condition or recover.

EXAMPLE 22 A patient suffering from paralysis attack. A carboxylic acid or carboxylic acid isostere of a ring N-heterocyclic or pharmaceutical compositions comprising the same, is administered to the patient. The patient is expected to improve his condition or recover.

EXAMPLE 23 A patient suffering from Parkinson's disease. A carboxylic acid or isostere of carboxylic acid of an N-heterocyclic ring or pharmaceutical compositions comprising the same, is administered to the patient. The patient is expected to improve his condition or recover.

EXAMPLE 24 - A patient suffering from Alzheimer's disease.

EXAMPLE 25 A patient who suffers from a neuropathy, peripheral.

EXAMPLE 26 A patient suffering from amyotrophic lateral sclerosis. A carboxylic acid or isostere of carboxylic acid of an N-heterocyclic ring or pharmaceutical compositions comprising the same, is administered to the patient. The patient is expected to improve his condition or recover.

EXAMPLE 27 A patient suffering from a spinal injury. A carboxylic acid or isostere of carboxylic acid of an N-heterocyclic ring or pharmaceutical compositions comprising the same, is administered to the patient. It is expected that; the patient improves his condition or recovers.

EXAMPLE 28 A patient at risk of suffering from a neurodegenerative disease or neurological disorder. A carboxylic acid or isostere of carboxylic acid of an N-heterocyclic ring or a pharmaceutical composition comprising the same, is administered to the patient.

It is expected that the patient will be prevented from certain or all the effects of the disease or disorder, or significantly improve their condition or recover from patients who were not pretreated.

The invention, which is thus described, it will be obvious that it can be varied in many ways. Such variations are not considered as a departure from the spirit and scope of the invention and all similar modifications are intended to be included within the scope of the following claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims

1. A compound having the formula (I) characterized because n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl Ci-Cio, C2.-C10 alkenyl or C2-C? Alkynyl; R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, wherein -R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain alkyl C? -C6, alkenyl or alkynyl straight or branched chain C2-C6, aryl , heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or straight or branched chain alkyl or alkenyl C? -C9; or a pharmaceutically acceptable salt, ester or solvate thereof; with the condition that: when D is a bond, and R2 is COOH, then Rx can not be substituted naphthyl; also with the condition that: when D is a bond, and n is 1, and R2 is COOH or CONHR3, then Ri is not hydroxy, methyl, ethyl, substituted or unsubstituted thioethyl, benzothiazole, substituted benzopyran, substituted benzopyrrole, substituted benzoxazole, substituted 5-membered heterocycle contains two heteroatoms of N and one heteroatom of S, or phenyl, phenylethyl, naphthyl, pyridyl, thienyl, -quinoline, tricyclic ring, aminoethyl, or substituted or unsubstituted benzyl; also with the condition that: when D is a bond, and n is 2, and R2 is COOH or phenylbutyl ester, then Rx is not substituted phenyl, or a substituted bicyclic ring containing two oxygen heteroatoms; also with the condition that: when D is a bond, and n is 1-2, and R2 is a carbocyclic or heterocyclic ring structure substituted or not. substituted, then Rx is not substituted or unsubstituted carbocycle or heterocycle, or hydroxy; also with the condition that: when D is a bond, and n is 1-2, and R2 is hydroxy, alkoxy, -S02 (phenyl), N (R3) 2, uncle or substituted alkylthio, -NCO, -P03 (Me) 2, or -NCOOC ( ethyl) phenyl, then Ri is not naphthalene, ethylene, substituted tricyclic ring, or substituted or unsubstituted phenyl; further with the proviso that: when D is C? -C3 alkyl or hexenyl, and R2 is hydroxyl, then Ri is not substituted or unsubstituted phenyl, or benzoimidazole; further with the proviso that: when D is methyl, and n is 1, and R2 is cyano or COOH, then Ri is not substituted phenyl; further with the proviso that: when D is methyl, and n is 1, and R2 is methoxy or N (R3) 2, then Ri is not methyl, ethyl, phenylethyl, substituted chloro-substituted oxirane, substituted aziridine wherein one of the carbons are replaced with an oxygen, substituted or unsubstituted propenyl, substituted phenyl, benzyl, or trifluoro-alkyl or C2-C3 alkenyl; also with the condition that: 0 when D is ethyl, and n is 2, and R2 is hydroxyl or N (R3) 2, then Ri is not naphthyl; also with the condition that: Jggjgfc - when D is propyl, and n is 1, and R2 is methoxy, then Ri is not ethylene, substituted cyano-ethyl, or substituted triethoxy-propyl; with the condition that: when D is not a bond and at least one of D and R2 contains at least one S or O atom, then Ri is not methyl or substituted phenyl.

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

3. The compound according to claim 1, characterized in that R2 is selected from the following group: where the atoms of the ring structure can optionally be substituted in one or more positions with R34. The compound according to claim 1, characterized in that the carboxylic acid or carboxylic acid isostere of R2 is selected from the group consisting of:

-COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN.

5. The compounds, (2S) -1- (phenylmethyl) sulfonyl-2-hydroxymethylpyrrolidine; (2S) -1- (phenylmethyl) sulfonyl-2-pyrrolidintetrazole.

6. A pharmaceutical composition, characterized in that it comprises: a) an effective amount of an N-linked sulfonamide of a N-heterocyclic carboxylic acid or carboxylic acid isostere; Y b) a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that the N-linked sulfonamide of N-heterocyclic or carboxylic acid carboxylic acid comprises a compound of formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl Ci-Cg, straight or branched chain alkenyl C2-Cg, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl Ci-Cio, alkenyl C2.-C? 0 or alkynyl C2-C? 0; R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isoster 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, straight or branched chain alkyl C-C6, straight or branched chain C2-C6 alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or straight or branched chain alkyl or alkenyl Ci-Cg; or a pharmaceutically acceptable salt, ester or solvate thereof;

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

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

10. The pharmaceutical composition according to claim 7, characterized in that R2 is selected from the group consisting of: -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (O) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN.

11. The pharmaceutical composition according to claim 7, characterized in that the N-linked sulfonamide of a N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-97.

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

13. The pharmaceutical composition according to claim 12, characterized in that the neurotrophic factor different from the formula (I) is selected from the group consisting of neurotrophic growth factor, brain-derived growth factor, glial-derived growth factor, ciliary neurotrophic factor. , insulin-like growth factor and active truncated derivatives thereof, acid fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5.

14. A method for treating a neurological disorder in an animal, characterized in that it comprises: administering to the animal an effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere to stimulate the growth of damaged peripheral nerves or promote neuronal regeneration.

15. The method according to claim 14, characterized in that the neurological disorder is selected from the group consisting of the cause of peripheral neuropathies by physical damage or disease state, physical damage to the brain, physical damage to the spinal cord, attack of paralysis associated with brain damage, and neurological disorders that are related to neurodegeneration. ..

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

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

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

20. The method according to claim 14, characterized in that the N-linked sulfonamide of a N-herecyclic carboxylic acid or isostere of cetrboxylic acid is non-immunosuppressive.

21. The method according to claim 14, characterized in that the N-linked sulfonamide of a N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl Ci-Cio, alkenyl C2.-C? 0 or alkynyl C2-C? 0; R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere 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, straight or branched chain alkyl, Ca-C6, straight-chain or branched C2-C6 alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or C de-C9 straight or branched chain alkyl or alkenyl; or a pharmaceutically acceptable salt, ester or solvate thereof;

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

2. 3 . The method according to claim 21, characterized in that R2 is selected from the following group: where the atoms of the ring structure can optionally be substituted in one or more positions with R3.

24. The method according to claim 21, characterized in that R2 is selected from the group consisting of: -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN.

25. The method according to claim 14, characterized in that the N-linked sulfonamide of a N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-97.

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

27. The method according to claim 26, characterized in that the neurotrophic factor different from the formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor derived from the brain, glial derived growth factor, ciliary neurotrophic factor, insulin-like growth factor and active truncated derivatives thereof, acid fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5.

28. A method for stimulating the growth of damaged peripheral nerves, characterized in that it comprises: administering to the damaged peripheral nerves a therapeutically effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere to stimulate or promote the growth of damaged peripheral nerves.

29. The method according to claim 28, characterized in that the N-linked sulfonamide of a N-herecyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

30. The method according to claim 28, characterized in that the N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain C C-C 9 alkenyl, straight or branched chain C 2 -C 9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl Ci-Cio, C2.-C10 alkenyl or C2-C? Alkynyl; R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, wherein R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain alkyl C? -C6, alkenyl or alkynyl straight or branched chain C2-C6, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or straight or branched chain alkyl or alkenyl Ci-C9; or a pharmaceutically acceptable salt, ester or solvate thereof;

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

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

33. The method according to claim 30, characterized in that R2 is selected from the group consisting of: -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN.

34. The method according to claim 28, characterized in that the N-linked sulfonamide of a N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-97.

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

36. The method according to claim 35, characterized in that the neurotrophic factor different from the formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor derived from the brain, glial derived growth factor, ciliary neurotrophic factor, insulin-like growth factor and active truncated derivatives thereof, acid fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5.

37. A method for promoting regeneration and neuronal growth in animals, characterized in that it comprises: administering to the animal a therapeutically effective amount of an N-linked sulfonamide of a N-heterocyclic carboxylic acid or neurotrophic carboxylic acid isostere to promote neuronal regeneration.

38. The method according to claim 37, characterized in that the N-linked sulfonamide of an N-heteocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

39. The method according to claim 37, characterized in that the N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl Ci-Co, C2.-C? 0 alkenyl or C2-C? Alkynyl? R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, wherein R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, straight or branched chain alkyl C? -C6, alkenyl or alkynyl straight or branched chain C2-C6, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or straight or branched chain alkyl or alkenyl Ci-Cg; or a pharmaceutically acceptable salt, ester or solvate thereof;

40. The method according to claim 39, characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, 0, S or N in any chemically stable oxidation state, wherein any of the atoms of the ring structure are substituted optionally in one or more positions with R3.

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

42. The method according to claim 39, characterized in that R2 is selected from the group consisting of: -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -C0NR3CN.

43. The method according to claim 37, characterized in that the N-linked sulfonamide of a N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-97.

44. The method according to claim 37, characterized in that it also comprises administering a neurotrophic factor different from the formula (I).

45. The method according to claim 44, characterized in that the neurotrophic factor different from the formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor derived from the brain, glial derived growth factor, ciliary neurotrophic factor, insulin-like growth factor and active truncated derivatives thereof, acid fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5.

46. A method for preventing neurodegeneration in an animal, characterized in that it comprises: administering to the animal a therapeutically effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere to prevent neurodegeneration.

47. The method according to claim 46, characterized in that the neurodegeneration is Alzheimer's disease.

48. The method according to claim 46, characterized in that the neurodegeneration is Parkinson's disease.

- "~ - 49. The method according to claim 46, characterized in that the neurodegeneration is amyotrophic lateral sclerosis.

50. The method according to claim 46, characterized in that the N-linked sulfonamide of an N-herecyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

51. The method according to claim 46, characterized in that the N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I): CH2) n where n is 1-3; R x is selected from the group consisting of hydrogen, straight or branched chain alkyl C 1 -C 9, straight or branched chain alkenyl C 2 -C 9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl C1-C10, alkenyl C2.-C? 0 or alkynyl C2-C? 0; R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere 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, straight or branched chain alkyl C? -C6 , C2-C6 straight or branched chain alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, where R4 is hydrogen or straight or branched chain alkyl or alkenyl C] .- C9; or a pharmaceutically acceptable salt, ester or solvate thereof;

52. The method according to claim 51, characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2 / O, S or N in any chemically stable oxidation state, wherein any of the atoms of the ring structure are substituted optionally in one or more positions with R3.

53. The method according to claim 51, characterized in that R2 is selected from the following group: where the atoms of the ring structure can optionally be substituted in one or more positions with R3.

54. The method according to claim 51, characterized in that R2 is selected from the group consisting of:

-COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (0) R3, - «ONHNHS02R3, -COHNS02R3, and -C0NR3CN. 52. The method according to claim 46, characterized in that the N-linked sulfonamide of a N-heterocyclic carboxylic acid is selected from the group consisting of compounds 1-97.

56. The method according to claim 46, characterized in that it also comprises administering a neurotrophic factor different from the formula (I).

57. The method according to claim 56, characterized in that the neurotrophic factor different from the formula (I) is selected from the group consisting of neurotrophic growth factor, growth factor derived from the brain, glial derived growth factor, ciliary neurotrophic factor, insulin-like growth factor and active truncated derivatives thereof, acid fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5.

58. A method for treating alopecia or promoting hair growth in an animal, characterized in that it comprises administering to the animal an effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere.

59. The method according to claim 58, characterized in that the N-linked sulfonamide of a N-herecyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

60. The method according to claim 58, characterized in that the N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere comprises a compound of formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl C1-C10, alkenyl C2.-C? 0 or alkynyl C2-C? 0; R2 is a carboxylic acid or an isostere of ceirboxylic acid; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere 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, straight or branched chain alkyl C? -C6 , C2-C6 straight or branched chain alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, where R4 is hydrogen or straight or branched chain alkyl or alkenyl Ci-Cg; or a pharmaceutically acceptable salt, ester or solvate thereof;

61. The method according to claim 60, characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in any chemically stable oxidation state, wherein any of the atoms of the ring structure are substituted optionally in one or more positions with R3.

62. The method according to claim 60, characterized in that R2 is selected from the following group: where the atoms of the ring structure can optionally be substituted in one or more positions with R3.

63. The method according to claim 60, characterized in that R2 is selected from the group consisting of: -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (O) R3, -CONHNHS02R3, -COHNS02R3, and -CQNR3CN.

64. The method according to claim 58, characterized in that the carboxylic acid or carboxylic acid isostere is selected from the group consisting of compounds 1-97.

65. A pharmaceutical composition, characterized in that it comprises: i) an effective amount of an N-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylic acid isostere to treat alopecia or promote hair growth in an animal; Y ii) a pharmaceutically acceptable carrier.

66. The pharmaceutical composition according to claim 65, characterized in that the N-linked sulfonamide of a N-herecyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive.

67. The composition according to claim 65, characterized in that the carboxylic acid or carboxylic acid isostere is a compound of formula (I): where n is 1-3; Ri is selected from the group consisting of hydrogen, straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a straight or branched chain alkyl C? -C10, C2.-C? 0 alkenyl or C2-C? Alkynyl? R2 is a carboxylic acid or a carboxylic acid isostere; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere 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, straight or branched chain alkyl C? -C6 , C2-C6 straight or branched chain alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or C02R4, wherein R4 is hydrogen or straight or branched chain alkyl or alkenyl d-Cg; or a pharmaceutically acceptable salt, ester or solvate thereof;

68. The composition according to claim 67, characterized in that R2 is a carbocycle or heterocycle containing any combination of CH2, O, S or N in any chemically stable oxidation state, wherein any of the atoms of the ring structure are substituted optionally in one or more positions with R3.

69. The composition according to claim 67, characterized in that R2 is selected from the following group: where the atoms of the ring structure can optionally be substituted in one or more positions with R3.

70. The composition according to claim 67, characterized in that R2 is selected from the group consisting of: -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, - CONH (O) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN. -

71. The composition according to claim 65, characterized in that the carboxylic acid or carboxylic acid isostere is selected from the group consisting of compounds 1-97.