CZ20004473A3 - Ureas and carbamates of N-heterocyclic carboxylic acids and carboxylic acid isosters - Google Patents

Abstract

The present invention relates to novel ureas and carbamates of N-heterocyclic carboxylic acids and carboxylic acid isosteres, a process for their preparation and use for the treatment of neurological disorders including physically damaged nerves and neurodegenerative diseases, and for the treatment of hair growth by neuroimmunophilin ligands, as is shown in the diagram.

Description

Ureas and carbamates of N-heterocyclic carboxylic acids and carboxylic acid isosteres

Application details

This application is a partial continuation of U.S. Patent Application Serial No. 60/087844 to Hamilton et al., Entitled Ureas and Carbamates of N-Heterocyclic Carboxylic Acids and Carboxylic Acid Isosters, filed Jun. 3, 1998.

Technical field

The present invention relates to novel ureas and carbamates of N-heterocyclic carboxylic acids and carboxylic acid isosteres, their preparation and use for the treatment of neurological disorders, including physically damaged nerves and neurodegenerative diseases, and for the treatment of alopecia and hair growth promotion.

BACKGROUND OF THE INVENTION

It has been found that picomolar concentrations of immunosuppressive agents such as FK506 and rampacyn stimulate neurite outgrowth in PC12 cells and sensory nerves, namely dorsal root ganglion cells (DKGB). Lyons et al., Proc. of Nati. Acad. Sci., Vol. 91, pp. 3191-3195, 1994. In all animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury and result in functional recovery in animals with sciatic nerve damage.

Several neurotrophic factors affecting the number of neurons in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer's disease results from a reduction or loss of nerve growth factor (RFN). Therefore, '5 τ

suggested to treat alzheimer's patients with exogenous nerve growth factor or other neurotrophic proteins such as neural brain transfer factor (FNMP), glial nerve transfer factor, ciliary neurotropic factor, and use neurotropin-3 to increase the survival time of degenerating neurons.

f The clinical application of these proteins, in various conditions of ^f neurological diseases, is hampered by delivery problems and bioavailability of nerve system target sites for large proteins. In contrast, immunosuppressive agents with neurotropic activity are relatively small and exhibit excellent bioavailability and specificity. However, when administered consistently, immunosuppressive agents exhibit many potentially serious side effects, including nephrotoxicity, such as glomerular filtration impairment and irreversible interstitial fibrosis (Kopp and Nephrol., 1, 162, 1991); neurological are autonomous tumors or non-localized headaches are non-specific (De. J. Med., 317, 861, 1987); and vascular hypertension with complications resulting therefrom (Kahan et al., N. Engl. J. Med., 321, 1725, 1989).

et al., J. Am. Soc. deficiencies, such as cerebral angina, such as Groen et al., N. Engl

Accordingly, there is a need for small molecule compounds that are useful for neurotrophic effects and for the treatment of neurodegenerative disorders.

Hair loss occurs in a variety of conditions. These conditions include male-type alopecia, age-old alopecia, local alopecia, diseases associated with skin-related disorders or tumors, and systemic disorders such as nutritional disorders and internal secretion disorders. Mechanisms causing hair loss are very complicated, but in some cases aging, genetic predisposition, male activation may contribute to them.

4 ·· · hormones, loss of blood supply to the hair follicles and abnormal scalp.

The immunosuppressive agents FK506, rapamycin and cyclosporin are well known as potent specific T-cell immunosuppressants, and are effective against transplant rejection after organ transplantation. Topical but not oral administration of FK506 has been reported (Yamamoto et al., J. Invest. Dermatol., 102, 160-164, _Line 1994; Jiang et al., J. Invest. Dermatol., 104, 523). up to 525,

1995) and cyclosporine (Iwabuchi et al., J. Dermatol. Sci., 9, 64-69 (1995)) stimulate hair growth depending on the dosage method. One form of hair loss of local alopecia is known to be associated with autoimmune activities; therefore, topically administered immune-modulating compounds are expected to prove their effectiveness in the treatment of this type of hair loss. Hair growth stimulating FK506 activities are the subject of an international patent application covering FK506 and hair growth stimulating compounds (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses the use of relatively large tricyclic compounds known for their immunosuppressive effects as hair revitalizing agents.

FK506 effects apříbuzných agents on hair growth and revitalization ^r are described in many U.S. patents (Goulet et al.,

U.S. Patent No. 5,258,389; Luly et al., U.S. Patent No. 5,457,111; > Goulet et al., U.S. Patent No. 5,189,042 and Ok et al.

208 241; Rupprecht et al., U.S. Patent No. 5,284,840; Organ et al., 5 et al., U.S. Patent No. 5,284,877). These patents cover FK506 and related compounds. Although they do not cover hair revitalization methods, I describe the known use of FK506 to affect hair growth. Similar to FK506 (and the variants covered by the patents in Honbo et al.), The compounds covered by these patents are relatively large. Furthermore, the cited patents deal with immune modulating compounds and

the use of these compounds in diseases associated with autoimmunity, in which the efficacy of FK506 compounds is well known.

Other US patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al., US Patent No. 5,342,625; Eberle, US Patent No. 5,284,826; Hewitt et al., US Patent No. 4,996,193). These patents also deal with compounds useful for the treatment of autoimmune diseases and cite the known use of cyclosporine and related immunosuppressive compounds for hair growth.

However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Thus, there is a need for small molecule compounds that are useful as hair revitalizing compounds.

SUMMARY OF THE INVENTION

The present invention relates to the surprising finding that ureas and carbamates of N-heterocyclic compounds containing carboxylic acid or carboxylic acid isosteres may be useful for the treatment of neurodegenerative disorders and for the treatment of alopecia and related disorders associated with hair loss. Thus, the invention provides a new class of compounds comprising acid particles or isomers thereof attached to the 2nd carbon of an N-heterocyclic urea derivative or carbamate derivative. These compounds stimulate neuronal regeneration and growth and are thus useful for the treatment of neurological disorders and neurodegenerative diseases. These compounds also promote hair growth and thus are useful for the treatment of hair loss disorders. A preferred feature of the compounds

The V 'of the present invention is that it has no significant immunosuppressive activity and / or is non-immunosuppressive.

A preferred embodiment of the invention is a compound of formula (I):

&

IN

AND

R ₂

Wherein n is 1 to 3;

R 1 and A are independently selected from the group consisting of hydrogen, C 1 -C 9 straight or branched alkyl chain, C 2 -C 9 straight or branched alkenyl chain, aryl, heteroaryl, carbocycle and heterocycle;

D is a bond or a C 1 -C 10 straight or branched alkyl chain, a C ₂ -C 10 alkenyl or a C ₂ -C ₁₀ alkynyl chain;

R ₂ is a carboxylic acid or carboxylic acid isoster;

wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or isosteric carboxylic acid is optionally substituted with one or more substituents selected from R ³ , wherein:

R ³ is hydrogen, thiocarbonyl, arylalkyloxy, cyano, mercapto, thioalkyl, branched alkyl hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, nitro, imino, alkylamino, aminoalkyl, alkylthio, sulfonyl; C1-C6 straight chain or a C ₂ -C 6 straight or branched

6.

alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle, and CO ₂ R ⁴ wherein R ⁴ is hydrogen or C 1 -C 9 straight or branched chain alkyl or alkenyl;

or a pharmaceutically acceptable salt, ester or solvate thereof; assuming that;

A and R 1 are not substituted with both hydroxy and oxygen to form a carboxy group, or A and R 1 are not substituted with both alkoxy and oxygen to form alkoxycarbonyl, or A and R 1 are not substituted with both amine and oxygen to form an amide;

provided that:

when R ₂ is COOH, then A and R are either hydrogen or phenyl;

provided that:

when n = l, Adjei bond, and R ₂ is COOH, and A is hydrogen, then Ri is not hydrogen, methyl, ethyl, isopropyl, t-butyl, octyl, chloroethyl, cyclohexyl, substituted or unsubstituted phenyl, phenylmethyl, phenylethyl, naftylenylmethyl , naphthylenylethyl, thiazolyl, alkoxythiazolyl, substituted or unsubstituted benzothiazolyl, quinoline, or thioalkyl;

provided that:

when D is a bond, and R ₂ is COOH, and A is 4-chlorophenyl, then Ri is not methoxymethyl;

provided that:

when n = 2, and D is a bond, and R ₂ is COOH, and A is hydrogen, then R 1 is not hydrogen, substituted or unsubstituted phenyl, or alkoxythiazolyl;

provided that:

when n = 1, and D is a bond, and R ₂ is CON (R ₃ ) ₂ , and A is hydrogen, then R 1 is not isopropyl, tert-butyl, cyclohexyl, cyano substituted alkyl, or substituted phenyl; provided that:

when n = l, Adjei bond, then R ₂ is not methoxy;

provided that:

when n = 1 or 2, and D is a bond, and R ₂ is hydroxy, then R 1 is not substituted phenyl; provided that:

when n = 1 or 2, and D is substituted or unsubstituted methyl, and R ₂ is hydroxy or methoxy and A is hydrogen, then R 1 is not substituted phenyl, hydrogen, methyl, ethyl, substituted propyl or hydroxy;

provided that:

when n = 2, and D is hydroxypentyl, and R ₂ is hydroxy, and A is hydrogen, then R 1 is not phenyl; provided that:

when n = 2 and D is ethyl, and R ₂ is N (R ₃ ) ₂ , then R 1 and A cannot be the same;

provided that:

when n = 1 and D is methoxy, and R ₂ is CON (R ₃ ) ₂ , and A is methyl, then R 1 is not benzyl;

provided that:

when n = 1, and D is methyl, and R ₂ is N (R ₃ ) ₂ , and A is hydrogen, then R 1 is not a hydroxy group;

provided that:

when D is C 1 -C 2 alkyl, and A is hydrogen, then R _T is not butyl.

A preferred embodiment of the invention is (2S) -1 (cyclohexyl) carbamoyl-2-pyrrolidine carboxylic acid.

Preferred embodiments of the invention are those wherein R ₂ is a carbocycle or heterocycle containing any combination of CH ₂ , O, S or N at any chemically stable oxidation stage, wherein any of the atoms of said ring structure are optionally substituted at one or more positions by R ³ .

Particularly preferred embodiments of the invention are those wherein R 2 is selected from the following group:

OH wherein the atoms of said ring structure may be optionally substituted at one or more positions by R ³ .

Another preferred embodiment of the invention is where R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ (R ³ ) 2, -OR ^3, -SR ^3, - NHCOR ^3, -N (R ³⁾ 2, -CON (R ³⁾ 2, -CONH (0) ^R3, -CONHNHSO2R ³ -COHNSO ₂ R ³ and CONR ³ CN.

Another preferred embodiment of the invention is a pharmaceutical composition comprising: an effective amount of a compound of formula (I); and a pharmaceutically acceptable and acceptable carrier. For neurotrophic compositions, they may also be administered with a neurotropic factor, or the factor may be different from the compound of formula (I) otherwise present in the composition.

Another preferred embodiment of the present invention is a method of promoting neuronal regeneration and growth in a mammal, comprising administering to the mammal or an animal an effective amount of N-heterocyclic carboxylic acid urea or carbamate or isosteres to stimulate the growth of damaged peripheral nerves or promote neuronal regeneration.

Another preferred embodiment of the present invention is a method of treating neurological disorders in animals, comprising administering to the animal an effective amount of urea or carbamate of the N-heterocyclic carboxylic acid or isosteres to stimulate the growth of damaged peripheral nerves or promote neuronal regeneration

Yet another preferred embodiment of the invention is a method of preventing neurodegeneration in animals, comprising administering an effective amount of urea or carbamate N-heterocyclic

a carboxylic acid or carboxylic acid isostere to an animal.

Yet another preferred embodiment of the invention is a method of treating alopecia or promoting hair growth in animals, comprising administering. an effective amount of the urea or Nf carbamate of the heterocyclic carboxylic acid or carboxylic acid isosteres to the animals.

<i ......

Brief description of the pictures

Figure 1 is a photograph of a sample of C57, 6 black mice before they were shaved for a hair regeneration experiment.

Figure 2 is a photograph of vehicle treated mice after 6 weeks.

. Figure 2 shows that less than 3% of the shaved area is covered with newly grown hair when applied (control). vehicle.

Figure 3 is a bar graph depicting the relative hair growth of shaved mice treated with N-heterocyclic carboxylic acids or carboxylic acid isostere at 1 pmol per milliliter three times a week. Hair growth was evaluated after 14 days of treatment.

Detailed Description of the Invention ·

Definition

Alkyl means a branched or unbranched saturated hydrocarbon chain containing a specified number of carbon atoms. For example, C1-C6 straight or branched chain alkyl hydrocarbon contains 1-6 carbon atoms and includes, but is not limited to substituents such as methyl, ethyl, propyl, ¹ '>

Isopropyl, butyl, isobutyl, tert-butyl, 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, wherein any of the carbon atoms of said alkyl are optionally replaced by O, NH, S or SO ₂ . For example, carbon atom 2 of n-pentyl can be replaced by 0 to form propyloxymethyl.

Alkenyl means a branched or unbranched unsaturated hydrocarbon chain containing a specified number of carbon atoms. For example, a C ₂ -C 6 straight or branched 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 ethynyl, propenyl, isopropenyl, butenyl, isobutenyl, tert-butenyl, n-pentenyl, n-hexenyl and the like. It is also within the scope of the present invention that alkenyl may also refer to an unsaturated hydrocarbon chain, wherein any of the carbon atoms of said alkenyl are optionally replaced by O, NH, S or SO ₂ . For example, carbon # 2 of 4-pentene can be replaced by O to form (2-propene) oxymethyl.

Alkoxy refers to the group -OR where R is alkyl as defined herein. Preferably, R is a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms.

The term carbocycle refers to an organic cyclic compound in which the cyclic backbone consists only of carbon atoms, while the term heterocycle refers to an organic cyclic compound in which the cyclic backbone contains one or more heteroatoms selected from nitrogen, oxygen or sulfur and which may or it need not contain carbon atoms.

···· rf

Thus, the term carbocycle refers to a carbocyclic compound containing the indicated number of carbon atoms. The term C 3 -C 8 cycloalkyl therefore refers to an organic cyclic substituent in which 3 to 8 carbon atoms form a 3, 4, 5, 6, 7 or 8-membered ring, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. When used herein, a carbocycle may also refer to a system of two or more cyclic rings that are linked to a compound, for example, bicyclic, tricyclic or other similarly formed substituent-forming bridges (e.g., adamantyl).

Aryl refers to an aromatic carbocyclic group having a single ring, for example a phenyl ring; multiple rings such as biphenyl; or multiple fused 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 substituents as defined above. The substituents attached to the phenyl ring from the aryl portion of the compound of formula (I) may be configured to be ortho-, meta- or para-.

Examples of typical aryl moieties included within the scope of the present invention may include, but are not limited to, the following:

ί ^ Ί

• ···

·· ·· »· · ·

Aralkyl refers to an alkyl or alkylene (alkenyl) chain which is substituted with an aryl, heteroaryl, carbocycle or heterocycle or alternatively one or more aryl, heteroaryl, carbocycles or heterocycle (s) which is / are substituted with alkyl or alkenyl ie. alkyl / alkylene which is substituted by Ar 'or' Ar group which is substituted by alkyl / alkylene.

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 in 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 ζ substituted with one or more of the groups defined above.

Further, bi- or tricyclic heteroaryl compounds may contain at least one ring which is either fully or partially saturated.

As will be appreciated by one skilled in the art, such heterocyclic compounds may exist in several isomeric forms, all of which are covered by the present invention. For example, • ················

The 1,3,5-triazine group is isomeric to the 1,2,4-triazine group. Such positional isomers should be considered within the scope of the present invention. Similarly, heterocyclic or heteroaryl groups may be linked to other particles in the compounds of the present invention. The attachment point (s) to these other particles should not be construed as limiting the scope of the invention. Thus, for example, a pyridyl particle may be bonded to other groups via the 2-, 3-, or 4-position of the pyridyl group. All such configurations should be understood as being part of the scope of the present invention.

Examples of heterocyclic or heteroaryl particles (compounds) included within the scope of the present invention may include, but are not limited to, the following:

"Halogen" means at least one fluoro, chloro, bromo, or iodo particle.

The term pharmaceutically acceptable salt, ester or solvate refers to salts, esters or solvates of the subject compounds having the desired pharmacological effects and which are neither biologically nor otherwise undesirable. Salts, esters or solvates can be formed with inorganic or organic acids such as acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphrates, camphorsulfonates, cyclopentane propionates, digluconates, dodecylsulfate, ethanesulfonates, ethanesulfonates, ethanesulfonates, gluconates, glycerophosphates, hemisulphates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2f-hydroxyethane sulfonates, lactates, maleates, methanesulfonates, naphthylates, 2-naphthalenesulfonates, nicotinates, oxalates, sulfates, thiocyanates, thiocyanates. Basic salts, esters 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, organic base salts such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and amino acid salts 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 chloride, bromides and iodides; 2) dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;

3) alkyls myristyls long chain halides such as and stearyls substituted such as chloride, bromide are decyls, lauryls, with one or more and iodide; 4) aryl or arylalkyl halides such as benzyl and phenethyl bromide and others

The compounds of the invention may have at least one asymmetric center and thus may be produced as mixtures of stereoisomers or as individual enantiomers or diastereomers. The individual stereoisomers may be obtained using an optically active initial; material, by redissolving the racemic or non-racemic mixture of the intermediate at some convenient stage in the synthesis, or by redissolving the compound of formula (I). It will be understood that individual stereoisomers as well as mixtures (racemic or non-racemic) of stereoisomers are included within the scope of the present invention. The S-stereoisomer at atom 1 of the compound of formula (I) is the most preferred embodiment of the invention.

Stereoisomers are isomers that have spatial arrangement of atoms.

differ only in the way

Isomers are different compounds having the same molecular formula and containing cyclic isomers such as (iso) indole and other isomeric forms of the cyclic moieties.

Enantiomers are paired stereoisomers that are a non-overlapping mirror image of one another.

Diastereoisomers are stereoisomers that are not a mirror image of one another.

Racemic mixture means a mixture containing equal portions of the individual enantiomers. A non-racemic mixture is a mixture containing unequal portions of the individual enantiomers or stereoisomers.

Isosters are different compounds that have different molecular formulas but exhibit the same or similar properties. For example, tetrazole is a carboxylic acid isoster because it mimics the properties of a carboxylic acid, although both have very different molecular compositions. Tetrazole is one of many possible isosteric substitutions for carboxylic acids. Other carboxylic acid isosteres contemplated by the present invention include -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ (R ³ ) 2, -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2, -CON (R ³ ) 2, -CONH (O) R ³ , -CONHNHSO ² R ³ , COHNSO ² R ³ , and -CONR ³ CN.

In addition, the carboxylic acid isosteres may contain 5-7 membered carbocycles by a combination of CH ₂ , O, oxidation structure steps, or heterocycles containing any

S or N in any chemically stable wherein any of the atoms or are and in one substituted. The following structures exemplify the preferred carbocyclic isosteres contemplated by the present invention.

optionally said circular multiple positions do not limit heterocyclic

HN — N

COOH

J!

N - N fc

In which atoms of said ring structure may be optionally substituted at one or more positions by R, the present invention contemplates that when chemical substituents are added to the carboxyl isosteres, the newly formed compound retains the carboxyl isostere properties. The present invention contemplates that when a carboxylic isoster is optionally substituted with one or more groups selected from R ³ , then the substitution cannot eliminate the carboxylic acid isostere properties of the newly formed compound. The present invention contemplates that the placement of one or more R ³ substituents on a carbocyclic or heterocyclic carboxylic acid isoster should not be allowed on one or more of the atom (s) which maintain (s) or is / are necessary for the carboxylic acid isosteric properties of a newly formed compound, if such substituent (s) would destroy the carboxylic acid isosteric properties of the newly formed compound.

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

The term preventing neurodegeneration as used herein includes the ability to stop or prevent neurodegeneration in patients with a fresh diagnosis of having a neurodegenerative disease, or at risk of developing a new degenerative disease, and to stop or prevent further neurodegeneration in patients already suffering from or experiencing symptoms of neurodegenerative disease. wherein the compounds are co-administered.

The term treatment as used herein covers any treatment of the disease and / or its conditions in animals, especially humans, and includes:

(i) preventing a disease and / or conditions occurring in a subject that may prevent the disease and / or its conditions but are not yet diagnosed as having a disease;

(ii) inhibiting the disease and / or its conditions, i. stopping their development; or (iii) relieving the disease and / or its conditions, i. causing regression of the disease and / or its conditions.

The system used to name the compounds of the present invention as shown below uses an example of a compound of formula I as an example.

'N

D '

N '

Ri

A compound of the present invention, particularly of Formula I, wherein n is 1, X is O, D is a bond, R 1 is 1,1-dimethylpropyl, and R ₂ is -CN, is named (2S) -1- (1,2-dioxo 3). 3-dimethylpentyl-2-pyrrolidinecarbonitrile.

Alopecia refers to inadequate hair growth and partial or total hair loss, including but not limited to androgenic alopecia (male pattern baldness), toxic alopecia, senile alopecia, alopecia aerata, alopecia pelada, and trichothilomania. Alopecia ends when the phase cycle is interrupted. The most common phenomenon is a shortening of hair growth or anagen phase to stop cell growth. This results in an early onset of the catagen phase, and consequently a large number of hairs are in the telogen phase during which the hair follicles are separated from the papillae and the hair falls out. Alopecia has a number of causes including genetic factors, aging, local and systemic diseases, feverish conditions, mental stress, hormonal problems, and secondary effects of drugs.

The phase cycle refers to the life cycle of the hair follicles, and includes 3 phases:

(1) anagen phase, a period of active hair growth that lasts about 3 to 5 years with respect to a hair scalp; (2) a catagen phase, a period of growth stops and hair follicles atrophy, which lasts about a hair scalp 1 to 2 weeks, and (3) the telogen phase, the last period of hair to separate and eventually fall out, which in terms of hair scalp lasts about 3 to 4 months.

Normally 80 to 90% of the hair follicles are in the anagen phase, less than 1% are in the catagen phase, and the rest is in the telogen phase. They have hair in the telogen phase. uniform diameter with slightly bulbous

unpigmented roots. In contrast, in the anagen phase, hair has a large colored bulb on its roots.

Hair Growth Promotion refers to the maintenance, development, stimulation, acceleration or revitalization of germs.

Treatment of alopecia refers to:

(i) preventing alopecia in animals that may be susceptible to alopecia, and / or (ii) halting, slowing or reducing alopecia, and / or (iii.) promoting hair growth, and / or (iv) prolonging the anagenic phase of the hair cycle , and / or (v) converting the fluff to growth as adult hair. Adult hair is a coarse, pigmented, long hair in which the hair follicle is placed deep in the skin. Hair fluff, on the other hand, is a fine, thin, unpigmented short hair in which the hair bulb is superficially located in the skin. As alopecia progresses, hair changes from adults to fuzzy type.

The term neurotrophic as used herein includes, but is not limited to, the ability to stimulate neuronal regeneration or growth and / or the ability to prevent or treat neurodegeneration.

The term non-immunosuppressive refers to the inability of the compounds of the present invention to trigger an immune response when compared to controls such as FK506 or cyclosporin Ά. Assays for determining immunosuppression are well known to those of ordinary skill in the art. Specific non-limiting examples of well known assays include the PMA and 0KT3 assays, where mitogens are used to stimulate human peripheral blood lymphocyte (PKL) growth. Compounds added to such assay systems are evaluated for their ability to arrest such growth.

• · · · ·

Compounds described by the invention

The present invention relates to the surprising discovery that carboxylic acids or isosteric carboxylic acid compounds are neurotrophic and are capable of treating alopecia. Thus, a new class of compounds is provided. A preferred feature of the compounds of the present invention is that they do not induce any significant immunosuppressive activity.

Preferred compounds of the present invention contain carboxylic acid groups and other isosteric replacements of carboxylic acid groups, of which several examples are specified herein. Other isosteric substitutions of carboxyl group groups known to those skilled in the art of medical chemistry are included within the scope of the invention unless otherwise specified.

The neurotropic compounds of the invention may be periodically administered to a patient undergoing treatment for neurological disorders or for other reasons in which it is desirable to stimulate neuronal regeneration and growth, as well as in and neurological disorders of the Compound of this various peripheral neuropathy associated with non-regeneration. The invention may also be administered to non-human mammals for the treatment of various mammalian neurological disorders.

The novel compounds of the present invention have an excellent degree of neurotropic activity. This activity is useful in stimulating damaged neurons, promoting neuronal regeneration, preventing neurodegeneration, and treating several neurological disorders known to be associated with neuronal degeneration.

and peripheral neuropathies. Neurological disorders that may be treated include, but are not limited to:

trigeminal neuralgia, Palsia's disease, myopharyngeal neuralgia myasthenia, Bells gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, progressive hereditary ocular muscular atrophy, seizure, fracture or prolapse of intervertebral disc, canal spasm, throat plexus tick-borne neuropathy, such as lead-induced porphyria, or Gullain-Barré's peripheral "dapson, syndrome,

Alzheimer's disease and Parkinson's disease.

The above discussion regarding the utility and administration of the compounds described by the present invention also relates to the pharmaceutical compositions described by the present invention.

The term "pharmaceutically acceptable carrier" as used herein refers to any carrier, diluent, excipient, suspending agent, lubricant, adjuvant, vehicle, route of administration, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, flavor or sweetener. .

For this purpose, the compounds described by the present invention may be administered topically, rectally, orally, parenterally, by inhalation spray, nose, face, vaginally or via an implanted container in the form of doses containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parental as used herein includes subcutaneous, initravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal intracranal injection or infusion techniques.

For oral administration, the compounds described in the present invention can be delivered in any suitable dosage form known in the art. For example, the compositions may be formed into tablets, powders, granules, grains, chewable lozenges, capsules, liquids, aqueous suspensions or solutions, or similar dosage forms using conventional devices and techniques known in the art. Tablet dosage forms are preferred. Tablets may contain carriers such as lactose and cereal starch, and / or lubricating agents such as magnesium stearate. The capsules may contain diluents including lactose and dried cereal starch. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredients. '...

When preparing dosage forms containing the compounds described by this invention, the compounds may 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; absorbents such as silica; preservatives such as methylparaben, propylparaben and sodium benzoate; surfactants such as sodium lauryl sulfate, polysorbate 80, and the like; coloring agents such as F.D. & C. dyes and lacquers; flavorings; and sweeteners.

The compositions and methods of the invention may also utilize controlled release technologies. Thus, for example, the inventive compounds may be incorporated into the hydrophobic polymer network for controlled release over the course of days. Such controlled release films are well known in the art. Particularly preferred delivery systems are through the skin. Other examples of polymers commonly used for this purpose that can be used in the present invention include a non-degradable ethylene vinyl acetate copolymer and degradable lactic-glycolic acid copolymers which can be used externally or internally. Certain hydrogels such as poles (hydroxyethyl methacrylate) or poles (vinyl alcohol) may also be useful, but for shorter release cycles than other polymer release systems, such as those mentioned above.

To be therapeutically effective for targets in the central nervous t

In the system, the compounds of the present invention should readily penetrate the blood-brain barrier when administered peripherally. Compounds that cannot cross the blood-brain barrier can be effectively administered by the intraventricular route or other appropriate delivery system suitable for administration to the brain.

The compounds of the present invention may be administered in the form of a sterile injectable preparation, for example, an injectable aqueous or oleaginous suspension. These suspensions may be formed according to techniques known in the art using suitable humectants or suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringr's solvent, and isotonic. sodium chloride solution. In addition, sterile, stable oils are conventionally employed as a solvent or suspending medium. For this purpose, any stable non-irritating oil may be employed including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, in particular

Their polyoxyethylated versions are useful in the preparation of injections. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

The compounds of the invention may also be administered, rectally in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The compounds of the invention may also be administered topically, particularly when the symptoms to be treated include organs readily locally accessible, including neurological disorders of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas.

For topical application to the eye, or ophthalmic use, the compounds may be formulated as a micronized suspension in isotonic, pH adjusted, sterile saline or, preferably, as solutions in isotonic, pH adjusted, sterile saline, with or without preservatives such as benzylalkonium chloride. . Alternatively, the compounds for ophthalmic use may be formulated as an ointment such as petrolatum.

For topical application of the skin, the compounds may be formed into a suitable ointment containing the compound suspended or dissolved therein, for example, in admixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene and polyoxypropylene emulsifying wax and water.

• · · „„ „„ * * * * * * * * * * * *

Alternatively, the compounds may be formed into a suitable lotion or cream containing the active compound suspended or dissolved therein, for example in admixture with one or more of the following: petroleum oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.

Topical application to the lower gastrointestinal tract may be in the form of rectal suppositories (see above) or in an appropriate enema form.

Prescription dose levels of from about 0.1 mg to about 10,000 mg of the active ingredient of the compound are useful in the treatment of the above conditions, with a preferred level from about 0.1 mg to 1000 mg. The amount of active ingredient that may be combined with the carrier material in the manufacture of a single dose will vary depending upon the host treated and, in particular, the route of administration. Generally, in vitro the resulting dose effect provides useful guidance on the correct doses administered to a patient. Studies in Animal Models are also Useful Methods for determining the correct dosage level are well known in the art.

However, it is understood that the specific dosage level for each individual patient depends on a number of factors including the activity of the individual compounds used, age, body weight, general health, sex, nutrition, time of administration, elimination rate, combination of drugs and severity administration.

To effectively treat alopecia or promote hair growth, the compounds used in the inventive method must easily reach the target areas. For this purpose, the compounds are preferably administered topically through the skin.

{'·· ·· • · · 9

···· • · ·

For topical application of the skin, the compounds may be formed into suitable ointments containing suspended or dissolved compounds, for example, a mixture of one or more of mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene and polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds may be formed into a suitable lotion or cream containing a suspended or dissolved active compound, for example, in a mixture of one or more of petroleum oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The revitalizing compounds may be administered with other hair agents. The specific dose levels of the other hair revitalizing agents depends on the factors mentioned above and the efficacy of the drug combination. The present invention also contemplates other routes of administration known in the art of pharmacy.

Specific embodiments of the inventive compounds are set forth in Table I. The present invention contemplates the use of the compounds of Table I below in compositions and methods for preventing and / or treating neurological disorders in animals, and their use in compositions and methods for treating alopecia and promoting hair growth in animals. , and all other uses proposed in this specification.

Table I

C. η D R2 AND Rl 1 1 custody COOH H cyclohexyl 2 ' 1 custody COOH H α-methylbenzyl 3 1 custody COOH H 4-methylbenzyl 4 1 custody tetrazole H benzyl 5 1 custody SO ₃ H H α-methylbenzyl 6 1 ch ₂ COOH H 4-methylbenzyl 7 1 custody SO ₂ HNMe H Benzyl 8 1 custody CN H .alpha.-methylbenzyl 9 1 custody PO ₃ H ₂ H 4-methylbenzyl 10 2 custody COOH H benzyl 11 2 custody , COOH H N-methylbenzyl 12 2 custody COOH H 2-butyl 13- .. 2- - custody COOH .....-- .... H -. - 2-butyl 14 2 custody COOH. H cyclohexyl 15 Dec 2 custody PO ₂ Het., H isopropyl 16 2 custody P0 ₃ Propyl  H ' ethyl. · 17 2 custody PO ₃ (Et) ₂ H methyl 18 2 custody About me H tert.butyl 19 Dec 2 custody OEt H n-pentyl 20 May '2 custody Opřopyl H n-hexyl 21 1 custody Obutyl H cyclohexyl 22nd 1 custody Opentyl H cyclopentyl 23 1 custody Ohexyl H heptyl 24 1 custody  We are Ή n-octyl 25 1 custody SEt H n-hexyl 26 2 custody Spropyl H n-hexyl 27 Mar: 2 custody Sbutyl H n-hexyl 28 2 custody NHCOMe H n-hexyl 29 2 binding ‘ NHCOEt H 2-thienyl 30 1 ' CH ₂ N (Me) ₂ H adamantyl 31 .1 (CH ₂ ) ₂ N (Me) Et H adamantyl 32 1 (CH ₂ ) ₃ NIGHT (Me) ₂ H adamantyl

«Ae β β β β β β β β β β β 9 9 9 9 9 • · · · · · · · ·

99 '

Continuation of Table I

C. n D R2 AND Rl 33 1 _(CH2) 4 CONHMe H adamantyl 34 1 (CH ₂ ) p CONHEt H adamantyl 35 1 (CH ₂ ) ₆ CONHpropyl H adamantyl 36 1 custody CONH (0) Me H benzyl 37 1 custody CONH Et H α-methylphenyl 38 1 custody CONH (O) propyl H 4-methylphenyl 39. 2 custody COOH H benzyl 40 2 custody COOH H α-methylphenyl 41 . 2 custody COOH H 4-methylphenyl . 42 1 ch ₂ COOH Me cyclohexyl 43 . 1 (ch ₂ ) ₂ COOH Et cyclohexyl 4 4 1 (CH ₂ ) 3 COOH prop cyclohexyl . 45 1 _(CH2) 4 COOH but cyclohexyl 46 1 (CH ₂ ) 5 COOH H cyclohexyl , 47 1 (GH ₂ ) 6 COOH H  cyclohexyl , 4 8 1 (CH ₂ ) ₇ COOH H cyclohexyl 49 1 (CH ₂ ) ₈ COOH ’ H cyclohexyl 50 1 (CH ₂ ) 9 COOH H - cyclohexyl 51 1 (CH ₂ ) 10 COOH H cyclohexyl 52 1 c ₂ h ₂ COOH H cyclohexyl 53 1 2-OH, Et COOH H cyclohexyl 54 1 2-butylene COOH H cyclohexyl 55 1 1-propyl COOH H cyclohexyl 56 1 tert-butylCOOH H cyclohexyl 57 1 2-nitro- hexyl COOH H cyclohexyl '58 3 (CH ₂ ) ₂ CN H cyclohexyl 59 1 (CH ₂ ) 3 CN H cyclohexyl 60 3 custody CONHNHSO ₂ Me H benzyl 61 3 custody CONHNHSO ₂ Et H α-methylphenyl 62 3 custody CONHSO ₂ Me H 4-methylphenyl

Continuation of Table I

C. n D R2 AND Rl 63 2 custody CONHNHSO ₂ Et H phenyl 64 2 custody CON (Me) CN H α-methylphenyl 65 2 custody CON (Et) CN H 4-methylphenyl 66 1 (CH ₂ ) ₂ COOH H methyl 67 1 (CH2) 3 COOH H ethyl 68 ' 1 _(CH2) 4 COOH H n-propyl 69 1 (CH ₂ ) ₅ COOH H tert.butyl 70 1 (CH ₂ ) ₆ COOH H pentyl 71 1 (CH ₂ ) ₇ COOH . H hexyl 72 1 (CH2) 8 COOH H heptyl 73 1 (CH ₂ ) ₉ COOH H octyl 74 1 (CH _Z) ίο COOH H nonyl 75 1 C ₂ H ₂ COOH Ή cyclohexyl • * 76 1 custody 1-N H cyclohexyl 1 \ u <HN —N 77 1 custody I- ^X N H adamantyl 1 \ // <HN— N 78 1 custody 1-N H 1,1-dimethylp i \ //

HN - N bond y ¹ '

N //

HN — N trimethoxyphenyl

Continuation of Table I

No. n D R2

N.

0 1 bond i — X — NH COOH

1 binding

Λ ^N \

ÁY of ^{N —} NH

COOH

R1 cyclohexyl adamantyl

1 binding

1,1-dimethylpropyl ·

1 binding

1 binding

1 binding

P — NH COOH

H2 p — NH COOH

NH OH

N — N

NH OH

N-N trimethoxyphenyl cyclohexyl adamantyl Cl

I · ··

Continuation of Table I

No. n D R2

Rl

NH OH

1 binding

1,1-dimethylpropyl

Ν — N

NH OH

1 bond trimethoxyphenyl

Ν — N

1 binding

Me

N

N

Me cyclohexyl

1 adamantyl bond

NMe Me

1 binding

AND'

1,1-dimethylpropyl

N

Me Me

1 bond trimethoxyphenyl

Me

Me · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Continuation of Table I

No. n D R2

SH

Rl

1 binding

N, N / N = N cyclohexyl

SH

1 binding

Ν '\

adamantyl

N = N

SH

1 bond - | -N ^ N \ /

N = N

1,1-dimethylpropyl

SH

1

A-N N binding ξ \ /

N-N trimethoxyphenyl

cyclohexyl 99 · © · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Continuation of Table I

Rl adamantyl

OH

100 1 binding tÁ? O

101 1 binding

102 1 binding

OH

OH

1,1-dimethylpropyl trimethoxyphenyl cyclohexyl adamantyl

1,1-dimethylpropyl

OH

Continuation of Table I

No. n D

104 1 binding

105 1 binding

106 1 binding

107 1 binding

108 1 binding

103 1 binding

OH

WITH

R 1 trimethoxyphenyl cyclohexyl adamantyl

1,1-dimethylpropyl trimethoxyphenyl cyclohexyl

Rl

Continuation of Table I

No. n D R2

II

109 1 binding

NH adamantyl

110 1 binding

111 1 binding

C

112 1 binding

113 1 binding

114 1 binding

115 1 binding

1,1-dimethylpropyl trimethoxyphenyl

F cyclohexyl

F adamantyl

1,1-dimethylpropyl trimethoxyphenyl

É »• ·

Continuation of Table I

No. n D R2

116 1 binding

117 1 binding

118 1 binding

119 1 binding

120 1 binding

121 1 binding

122 1 binding

C

R1 cyclohexyl adamantyl

1,1-dimethylpropyl trimethoxyphenyl cyclohexyl adamantyl

1,1-dimethylpropyl 'UVs ·'.

300 3000

3 3 3 3)

Continuation of Table I

No. n D

123 1 binding

124 1 binding

125 1 binding

126 1 binding

127 1 binding

NH

NH

R 1 trimethoxyphenyl cyclohexyl adamantyl

1,1-dimethylpropyl

H trimethoxyphenyl

· 4

I 0 0 0 »00 40 0 ·

Continuation of Table I

No. n D R2

RI

128 1 binding

129 1 binding

cyclohexyl adamantyl

130 1 binding

131 1 binding

1,1-dimethylpropyl trimethoxyphenyl

132 1 binding

133 1 binding

cyclohexyl adamantyl il

About • · · ·

Continuation of Table I

No. n D R2

R1

134 1 binding

OH

1,1-dimethylpropyl

135 1 binding

OH trimethoxyphenyl

KN Et cyclohexyl

O — N .N Et

137 1 adamantyl binding

O - N .N Et

138 1 binding H

1,1-dimethylpropyl

O — N .N Et

139 1 binding I ξ H

O-N trimethoxyphenyl

Continuation of Table I

No. n D R2 • ·. · «

140 1 binding

H '

141 1 binding t_X

HN

142 1 binding

W 7 ^ΗΝ ~ Λ

143 1 binding

K ¹ '

HN

144 1 binding

N _in Me

S — N

145 1 binding

S — N

R1 cyclohexyl adamantyl

1,1-dimethylropyl trimethoxyphenyl cyclohexyl adamantyl flm 19 l 1 l

91

Continuation of Table I

No. n D R2

Rl

146 1 binding

Me _H

1,1-dimethylpropyl

S — N

147 . N Mp bond |

S-N trimethoxyphenyl

148 1 binding

149 1 binding

150 1 binding

cyclohexyl adamantyl

1,1-dimethylpropyl

151 1 binding ιΓ ^ Ύ

OH

H trimethoxyphenyl

9 9 ', 9 «9 9 9 ·

(Additionally, the acids and neurotrophic presented below:

A. ·

9999 »

Claimed or comparative carboxylic isosteres of the N-heterocyclic compounds of the invention that also exhibit significant effects and hair growth effects are shown

Slč. N D r ₂ L Ri AND 1 custody COOH 1,2-dioxoethyl 1,1-dimethylpropyl (B) 2 custody COOH 1,2-dioxoethyl 1,1-dimethylpropyl C 1 custody COOH SO ₂ benzyl D 1 ch ₂ OH 1,2-dioxoethyl 1,1-dimethylpropyl E 1 custody tetrazole 1,2-dioxoethyl 1,1-dimethylpropyl F 1 custody -CN 1,2-dioxoethyl 1,1-dimethylpropyl G 2 custody CONH ₂ 1,2-dioxoethyl 1,1-dimethylpropyl where Y and Z j are for of compound A-G 1 carbon atoms H 1 custody COOH 1,2-dioxoethyl 1,1-dimethylpropyl AND .1 custody COOH 1,2-dioxoethyl 1,1-dimethylpropyl

where Z is S for compound H and where Y is S for compound I.

.45 · · ·

9 9

Pharmaceutical compositions of the present invention

The present invention relates to pharmaceutical compositions comprising:

(I) an effective amount of a urea or carbamate of a N-heterocyclic acid or a carboxylic acid isostere, and (ii) a pharmaceutically acceptable carrier.

The present invention also relates to pharmaceutical compositions comprising:

(i) an effective amount of a urea or carbamate of a N-heterocyclic carboxylic acid or carboxylic acid isostere for treating neurodegenerative diseases, neurological disorders and nerve damage or promoting nerve growth in animals, and (ii) a pharmaceutically acceptable carrier.

The present invention also relates to pharmaceutical compositions comprising:

(i) an effective amount of a urea or carbamate of a N-heterocyclic carboxylic acid or carboxylic acid isostere for treating alopecia or promoting hair growth in animals, and (ii) a pharmaceutically acceptable carrier.

Neurotropic agents, the compounds may be administered with other neurotropic agents such as neurotropic growth factor, brain growth factor, glial growth factor, ciliary neurotropic factor, insulin growth factor and their active, derived derivatives, acidic fibroblast growth factor, basic fibroblast growth factor, > 3443

Ο 7 ςι ο

3 ’

Ο ICO

34 30 »» ‘3 3 ~ i Ο 3 7 3 7‘ 3 5 3 7 3 3

7 * 7 3 7 7 3

3 3 3 7 4

Dest ς> 3 0.0 Ο 7 0 'ίο platelet growth factors, neurotropin-3 or neurotropin 4/5. The dosage level of other neurotrophic agents depends on the previously noted factors and the neurotropic efficacy of the combination.

The methods of the present invention

The present invention relates to the use of any of the compounds described herein for the preparation of a medicament for the treatment of diseases such as peripheral neuropathy caused by physical injury or disease, physical brain damage, spinal cord physical injury, stroke associated with brain damage, Alzheimer's disease, Parkinson's disease and amyotropic lateral sclerosis. . The present invention also relates to the use of carboxylic acid compounds and carboxylic acid isosteres for the treatment of the aforementioned neuropathies, neurological disorders and neurological damage.

The present invention also relates to a method of treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of an N-heterocyclic carboxylic acid urea or carbamate or carboxylic acid isosteres. The present invention also relates to the use of the newly formed compounds and compositions for the preparation of a medicament for treating alopecia or promoting hair growth in animals.

The inventive method is particularly useful for the treatment of male type of alopecia, age alopecia, alopecia aerata, alopecia due to skin or tumor disorders, alopecia resulting from cancer treatment such as chemotherapy or radiation, and alopecia resulting from systemic disorders such as nutritional disorders and disorders internal secretion.

· '·

However, it is also understood that the specific dosage level for each individual patient depends on various factors including the activity of the specific compounds employed, age, body weight, general health, sex, diet, time of administration, elimination rate, combination of drugs and severity of the individual. the disease or disorder being treated and the method of administration.

MPTP model of Parkinson's disease in mice

MPTP injury of dopominergic neurons in mice was used as an animal model of Parkinson's disease. Four weeks old

... male CD1 white mice were dosed intraperitoneally with 30 mg / kg MPTP for 5 days. The inventive compounds (4mg / kg) or vehicle were administered subcutaneously with MPTP for 5 days, as well as for another 5 days following stopping MPTP administration. 18 days after MPTP administration, the animals were

Λ - sacrificed, striatum was decapitated and homogenized. To quantify the survival and recovery of dopominergic neurons, immunostaining of the sagittal and coronary parts of the brain with anti-tyrosine hydroxylase Ig was performed. In comparison to intact animals, significant loss of functional dopominergic endpoints was observed in animals treated with MPTP and vehicle. In another experiment, the test compounds were administered only sequentially. from «'» after MPTP damage. Thus, after the animals were given MPTP for 5 days, another 3 days elapsed before the 8th day of oral drug administration. The animals were treated with the inventive compounds (0.4 mg / kg), administered orally, once a day for a total of 5 days. On day 18, the animals were sacrificed and analyzed as above. Table II represents the percent recovery of dopominergic neurons in the first (co-dosed) sample

Animals to which carboxylic acid compounds or carboxylic acid isosteres were administered.

Table II, below, shows the significant neuroregenerative effect of the inventive carboxylic acid compounds or carboxylic acid isosteres of related compounds and represents the neurotropic ability of carboxylic acid isosteres as a group phenomenon that injured animals receiving carboxylic acid compounds or carboxylic acid isosteres show a marked recovery of dyed TH of dopominergic neurons.

Table II Compound - MPTP neurodegenerative model AND % Recovery 26.7% Compound (B) it is not defined Compound C 2 4.4 % Compound D '23, 2 O O Compound E 19, 6 % Compound F 34.1 % Compound G 46, 5 % Compound H _: 14.0 % Compound AND it is not defined

Percentage of striatal innervation density was quantified in brain parts using anti-tyrosine hydroxylase immunoglobulin, which is indicative of functional dopominergic neurons. A 23% striatal innervation density in animals pretreated only with vehicle administered orally during vehicle treatment indicates normal intact striatal tissue. The striatal innervation density was reduced to 5% in animals pretreated with MPTP given vehicle during oral treatment, suggesting MPTP-induced damage.

ř *

Surprisingly, the striatal innervation density increased to 8-13% in MPTP-pretreated animals administered orally during treatment with 0.4 mg / kg of the compounds of the invention, suggesting substantial neuronal regeneration following MPTP-induced damage.

In Vivo Hair Formation Test on 6 Black C57 Mice Black C57 mice were used to demonstrate the hair revitalizing properties of ureas and carbamates of N-heterocyclic carboxylic acids or carboxylic acid isosteres. The authors now refer to the paintings. Figures 1 and 2 depict 6 black C57 mice, approximately 7 weeks old, having a shaved area of about 5 cm x 5 cm in their hindquarters, from which all hairs are removed. Care was taken not to cut or scuff the underlying layers of skin. As the pinkish skin color suggested, the animals were in an anagene growth phase. Referring to Figure 2, 4 animals from the group were treated by topical administration of 20% propylene glycol vehicle (Figure 2) or related compounds dissolved in the vehicle. Animals were treated with vehicle or N-heterocyclic carboxylic acids or isosteres every 48 hours (3 applications over 5 days) and hair growth allowed to proceed for 6 weeks. Hair growth was quantified by the percentage of shaved area covered with newly grown hair during this time period.

Figure 2 shows that vehicle-treated animals showed only little hair growth in spots or tufts, with less than 3% of the shaved area covered by new growth.

In contrast, Figure 3 shows that animals treated for 2 weeks with N-heterocyclic carboxylic acid compounds i.e. compound A, compound B and compound G show for two weeks

O

ť · «·

Compounds dramatic hair growth, covering more than 25% of the shaved area in all animals.

Figure 3 shows the relative hair growth in 6 shaved black mice from sample C57 after 14 days after being treated with N-heterocyclic carboxylic acids or carboxylic acid isosteres. The mice were shaved on an area of about 5 cm from which all hairs were removed. Progressed _e . Take care not to cut or rub the skin layers lying under the hair. Compounds at a concentration of 1 pmol per milliliter were gently applied to the shaved area of mice (5 mice per group) three times a week. Hair growth was evaluated 14 days after the start of treatment with the compounds. The relative scale for assessing hair growth was as follows:

= no growth,.

= start of growth in small tufts, 1 *.

. = hair growth covering <25% of the shaved area,

=. hair growth covering> 25% of the shaved area but less than 50% of the shaved area, =: hair growth covering> 50% ‘of the shaved area but less than 75% of the shaved area,.

The following examples explain the preferred embodiment of the present invention and, at the same time, are not to be construed as limiting the present invention. All molecular weights of polymers express average molecular weights. Unless otherwise indicated, all percentages are based on percent by weight of the final delivery system or formulation prepared and all add up to 100% by weight.

• <ř • 51 j. ···· • · · · · · • · · · Examples of use invention The compounds of the invention can be prepared by various synthetic steps using established chemical transformations. An exemplary general method for synthesizing the present compounds is described in U.S. Pat Diagram I. Scheme I ^ Ň ^ ScOÓMe H ' Cykolhexyl ^- ^ / ^^ COOMe ---- Isocyanate ^1: -► HN ^^ O LiOH / MeOH CH ₂ Cl ₂ , Et ₃ N 1

COOH

O

HN

i ·· ·· ··· · · · · · · · · · · · · · · · · · · · · · · · ·

Example 1 (Compound 1)

Synthesis of (2S) -1- (N-cyclohexylcarbamoyl) pyrrolidine-2-carboxylic acid

a. Methyl (2S) -1- (N-cyclohexylcarbamoyl) pyrrolidine-2-carboxylate.

A mixture of cyclohexyl isocyanate (3.88 g, 31 mmol), L-proline hydrochloride ester (5.0 g, 30.19 mmol) and triethylamine (9 mL) in methyl chloride (150 mL) was stirred at room temperature overnight. The reaction mixture was washed with 1 x 100 mL 1 N HCl and 1 x 100 mL water. The organic phase was dried,

concentrated and cleaned in silica gel column (50 O Ό EtOAc / hexane) obtaining urea as a thick oil NMR (CDCl 3, 400 MHz): d 1.09 to 1.15 (m, 3H) 1.33 (m, 2H) 1.68 (m, 3H), 1.93-2.05 (m, 6H) 3.33 (m, 1H), 3.43 (m, 1Ή) 3.73 (with,

3H), 4.39 (m, 1H), 4.41 (m, 1H).

b. (2S) -1- (N-cyclohexylcarbamoyl) pyrrolidine-2-carboxylic acid.

Methyl (2S) -1- (N-cyclohexylcarbamoyl) pyrrolidine-2-carboxylic acid (3.50 g) was dissolved in methanol (60 mL), cooled to 0 ° C and treated with 2N LiOH (20 mL). After stirring overnight, the mixture was partitioned between ether and water. The ether layer was removed and the aqueous layer was acidified (pH 1) with 1N

HCl and extracted with methylene chloride. Drying and removal of solvent gained a 2.20 g product as a white solid, ^{X is} H

NMR (CDC1; s, 400 MHz): d 1, 14 to 1.18 (m, 3H) 1, 1.36 to 1.38 (m, 2H), 1.71 up to 1.75 (m, 3H), 1 , 95 up to 2.04 (m, 5H), 2.62 (m, 1H), 3.16 (m, 1H), 3.30-3.33 (m, 1H), 3.67 (m, 1H) l, 38 (br, 1H), 4.46 (m, 1 H).

···· • ..

··· • ···

9.

9949 9 9 9

4 4

4 «• 9

Example 2

Lotions containing the following composition may be prepared.

(%) 95% ethanol 80.0 N-heterocyclic urea or carbamate derivative carboxylic acid or carboxylic acid isosteres 10.0 α-tocopherol acetate 0.01 Ethylene oxide (40 moles) solidified addition products castor oil 0.5 Cleaned water 9.0 Fragrance and dye According to needs

To 95% ethanol is added a urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, α-tocopherol acetate, ethylene oxide (40 moles) hardened castor oil addition product, fragrance and colorant. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain transparent liquid lotion.

Daily 5 or 5 ml of lotion may be applied once or twice to a site showing marked baldness or alopecia.

Example 3 • fe

Lotions containing the following composition may be prepared.

(%) 95% ethanol 80.0 N-heterocyclic urea or carbamate derivative carboxylic acid or carboxylic isosteres acid 0, 005

• ·

Hinokitol 0.01 Ethylene oxide (40 moles) castor oil reinforced addition products 0, 5 Cleaned water 19, 0 Fragrance and dye According to needs

To 95% ethanol is added a urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isostere, α-tocopherol acetate, ethylene oxide (40 moles) hardened castor oil addition product, fragrance and colorant. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain transparent liquid lotion.

The lotion may be sprayed once to 4 times a day at a site that exhibits pronounced baldness or alopecia.

Example 4

An emulsion can be prepared from phase A and phase B having the following composition.

Phase A (%) Whale wax 0.5 Cetanol 2,0 Vaseline 5.0 Skvalan 10, 0 Polyoxyethylene monostearate (10 moles) 2,0 Sorbitan monooleate 1.0 N-heterocyclic urea or carbamate derivative carboxylic acid or carboxylic isostere acid 0.01

«,

Phase B % Glycerine 10.0 Cleaned water 69, 0 Aroma, colorant and preservative According to needs

Phase A and Phase B are heated one after the other, melted and maintained at 80 ° C. The two phases are then mixed and cooled to room temperature with stirring to obtain an emulsion.

The emulsion can be sprayed on spots of severe baldness or alopecia one to four times a day.

Example 5

A cream can also be prepared from phase A and phase B having the following composition. /

Phase A (%) Liquid paraffin 5.0 Cetostearol 5, 5 Vaseline 5.5 Glycerin monostearate 33.0 Polyoxyethylene (20 moles) 2-octyldodecyl ether 3.0 Propylparaben 0, 3 Phase B (%) N-heterocyclic urea or carbamate derivative carboxylic acids or carboxylic isosteres of acids 0.8 Glycerine 7.0 Dipropylene glycol 20, 0 Polyethylene glycol, 4000 5, 0 Sodium hexametaphosphate 0.005 Cleaned water 44,895

t • · ♦ · · · ·

···· ·· ··

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 once or four times a day to areas affected by severe baldness or alopecia.

Example 6

A liquid comprising the following composition may be prepared.

(%) Polyoxyethylenebutyl ether 20.0 Ethanol 50.0 Urea derivatives or carbamates of N-heterocyclic carboxylic acid or carboxylic isostere of acids 0.001 Propylene glycol 5.0 Polyoxyethylene derivative of hardened castor oil (80 moles of ethylene oxide addition product) 0.4 Scent According to needs Cleaned water According to needs

To the ethanol is added polyoxyethylene butyl ether, propylene glycol, a polyoxyethylene derivative of hardened castor oil, and a urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isostere and odor. The resulting mixture was stirred and purified water was added to obtain a liquid.

• ♦ · · · · · · · · ·

The liquid can be applied to sites affected by severe baldness or alopecia one to four times a day.

Example 7

A shampoo containing the following composition may be prepared.

(%) Sodium lauryl sulfate 5, 0 Triethanolamine lauryl sulfate 5.0 Betainelauryldimethylaminoacetate 6, 0 Ethylene glycol distearate 2,0 Polyethylene glycol 5, 0 N-heterocyclic urea or carbamate derivative carboxylic acid or carboxylic isosteres acid 5.0 Ethanol '. 2,0 Aroma,, \ _t 0.3 Cleaned water 69.7

To 69.7 g of purified water was added 5.0 g of sodium lauryl sulphate, 5.0 g of triethanolamine lauryl sulfate, 6.0 g of betaine lauryl dimethylaminoacetate. Thereafter, the mixture obtained by adding 5.0 g of urea derivative or carbamate of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, 5.0 g of polyethylene glycol and 2.0 g of ethylene glycol distearate in 2.0 g of ethanol is further stirred, and 0.3g of fragrance is then added. The resulting mixture is heated and then cooled to obtain a shampoo. *.

The shampoo can be applied to the scalp once or three times a day. '• · · ·

Example 8

The patient suffers from old age alopecia. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, or a pharmaceutical composition thereof, can be administered to a patient. Increased hair growth is expected to occur after treatment.

Example 8

The patient suffers from male type of alopecia. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, or a pharmaceutical composition thereof, can be administered to a patient. Increased hair growth is expected to occur after treatment.

Example 10

The patient suffers from local alopecia. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, or a pharmaceutical composition thereof, can be administered to a patient. Increased hair growth is expected to occur after treatment.

Example 11

The patient suffers from hair loss due to skin damage. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, or a pharmaceutical composition thereof, can be administered to a patient. Increased hair growth is expected to occur after treatment.

... $

Example 12. The patient suffers from hair loss due to tumors. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres or the pharmaceutical.

the composition containing it can be administered to a patient. Increased hair growth is expected to occur after treatment.

Example 13

The patient suffers from hair loss due to systemic disorders such as nutritional disorders or internal disorders> 1 '. ^: 'secretion. N-heterocyclic urea or carbamate derivative ^; the carboxylic acid or carboxylic acid isosteres, or a pharmaceutical composition thereof, can be administered to a patient. Increased hair growth is expected to occur after treatment. ,

Example 14

The patient suffers from hair loss due to chemotherapy. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres, or a pharmaceutical composition thereof, can be administered to a patient. Increased hair growth is expected to occur after treatment.

Example 15

The patient suffers from hair loss due to radiation. The urea or carbamate derivative of the N-heterocyclic carboxylic acid or carboxylic acid isosteres of the composition containing it may be administered or pharmaceutical to the patient.

Increased hair growth is expected to occur after treatment.

Example 16. .

The patient suffers from a neurodegenerative disease. It is administered a urea derivative or carbamate of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

Example 17

The patient suffers from a neurological disorder. It is administered a urea derivative or carbamate of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

Example 18

The patient suffers from stroke, or contains N-heterocyclic carboxylic acid carbamate. The patient is expected to cure.

Example 19, e

It is administered a urea or carboxylic acid derivative or an isostere pharmaceutical composition which improves the patient's condition or

The patient suffers from Parkinson's disease. It is administered a urea derivative or carbamate of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

Example 20

The patient suffers from Alzheimer's disease. It is administered a urea derivative or carbamates of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

Example 21

The patient suffers from peripheral neuropathy. It is administered a urea derivative or carbamates of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

»• 3 ··

Example 22

The patient suffers from amyotrophic lateral sclerosis. It is administered a urea derivative or carbamates of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

Example 23

The patient suffered spinal injuries. It is administered a urea derivative or carbamates of an N-heterocyclic carboxylic acid or a carboxylic acid isostere or a pharmaceutical composition containing it. The patient is expected to improve or cure the patient.

Example 24

The patient is at risk of a neurodegerative disease or neurological disorder. It is administered prophylactically the carboxylic acid or carboxylic acid isoster of the N-heterocyclic ring or a pharmaceutical composition containing the same compound. The patient is expected to be protected from some or all of the effects of the disease or disorder, or to substantially improve his condition or to cure the patient against untreated patients.

The invention is thus described, it being understood that it can be varied in many ways. These variations should not be considered as departing from the spirit and scope of the invention, and all such modifications are intended to be included in the following claims.

Claims (71)

Applicants claim: 1. A compound of formula (I): (CH ₂ ) _n wherein n is 1 to 3 R 1 and A are independently selected from hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, aryl, heteroaryl, carbocycle and heterocycle; D is a bond or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or isosteric acid is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 straight or branched alkyl chain, C ₂ -C 6 straight or branched alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ , where R is ⁴ is hydrogen or a C1-C9 straight or branched alkyl or alkenyl chain; or a pharmaceutically acceptable salt, ester or solvate thereof; assuming that; _R and Ri are not substituted with both hydroxy and oxygen to form carboxy, or A and R ,, are both substituted alkoxy and oxygen to form alkoxycarbonyl, or A and Ri are not substituted with both amine and oxygen to form amide; provided that: when R ₂ is COOH, then A and R are either hydrogen or phenyl; provided that: when n = 1, and D is a bond, and R ₂ is COOH, and A is hydrogen, then R 1 is not hydrogen, methyl, ethyl, isopropyl, tert-butyl, octyl, chloroethyl, cyclohexyl, substituted or unsubstituted phenyl, phenylmethyl, phenylethyl , naphthylenylmethyl, naphthylenylethyl, thiazolyl, alkoxythiazolyl, substituted or unsubstituted benzothiazolyl, quinoline, or thioalkyl; provided that: when D is a bond, and R ₂ is COOH, and A is 4-chlorophenyl, then Ri is not methoxymethyl; provided that: when n = 2, and Ό is a bond, and R ₂ is COOH, and A is hydrogen, then R 1 is not hydrogen, substituted or unsubstituted phenyl, or alkoxythiazolyl; provided that: when n = 1, and D is a bond, and R ₂ is CON (R 3) ₂ , and A is hydrogen, then R 1 is not isopropyl, tert-butyl, cyclohexyl, cyano substituted alkyl, or substituted phenyl; / provided that: when n = l, and D is a bond, then R ₂ is not methoxy; provided that: When n = 1 or 2, and D is a bond, and R ₂ is hydroxy, then R 1 is not substituted phenyl; provided that: when n = 1 or 2, and D is substituted or unsubstituted methyl, and R ₂ is hydroxy or methoxy and A is hydrogen, then R 1 is not substituted phenyl, hydrogen, methyl, ethyl, substituted propyl or hydroxy; provided that: when n = 2, and D is hydroxypentyl, and R ₂ is hydroxy, and A is hydrogen, then R 1 is not phenyl; provided that: when n = 2 and D is ethyl, and R ₂ is N (R ₃ ) ₂ , then R 1 and A cannot be the same; provided that: when n = 1 and D is methoxy, and R ₂ is CON (R ₃ ) ₂ , and A is methyl, then R 1 is not benzyl; provided that: when n = 1, and D is methyl, and R ₂ is N (R ₃ ) ₂ , and A is hydrogen, then R 1 is not a hydroxy group; provided that: when D is C 1 -C ₂ alkyl, and A is hydrogen, then R 1 is not butyl. A compound according to claim 1, wherein R ₂ is a carbocycle or heterocycle containing any combination of CH ₂ , O, S or N at any chemically stable oxidation step, wherein any of the atoms of said ring structure are optionally substituted at one or more positions by R ³ . The compound of claim 1, wherein R _{2 is} selected from the following group: Wherein said atoms substituted in one or more ring structure may be a R ³ group. optional » A compound according to claim 1, wherein the carboxylic acid or carboxylic acid isoster of group R _{2 is} selected from the group consisting of -COOH, -SO 3 H, -SO ² NH ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ ( R ³⁾ 2, -OR ^3, -SR ^3, - NHCOR ^3, -N (R ³⁾ 2, -CON (R ³⁾ 2, -CONH (O) R ^3, -CONHNHSO2R ³ -COHNSO2R and ³ - CONR ³ CN. Compounds: (2S) -1- (cyclohexyl) carbamoyl-2-pyrrolidinecarboxylic acid, and compounds 2 to 151. 6. A pharmaceutical composition comprising: (a) an effective amount of a heterocyclic isomer of a carboxylic acid; and b) a pharmaceutically acceptable carrier. characterized by 1 c 1 of urea or N-carboxylic acid carbamate; or Pharmaceutical composition according to claim 6, characterized in that the urea or carbamate of the N-heterocyclic carboxylic acid or isosteric carboxylic acid comprises a compound of the general formula (I): And wherein n is 1 to 3 R 1 and A are independently selected from the group consisting of hydrogen, C 1 -C 9 straight or branched chain alkyl, C ₂ -C 8 straight or branched alkyl; JÍ · · · · Φ Φ Φ · · φ · · · φ φ Φ φ φ A Φ Φ branched alkenyl chain, aryl, heteroaryl, carbocycle or heterocycle; D is a bond or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 straight or branched alkyl chain, C ₂ -C 6 straight or branched alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ , wherein R ⁴ is hydrogen or C 1 -C 9 straight or branched alkyl or alkenyl chain ; or a pharmaceutically acceptable salt, ester or solvate thereof. A pharmaceutical composition according to claim 7, wherein R ₂ is a carbocycle or heterocycle containing any combination of CH ₂ , O, S or N in any chemically stable oxidation step, wherein any of the atoms of said ring structure are optionally substituted in one or more positions by R ³ . Pharmaceutical composition according to claim 7, characterized in that R ₂ is selected from the following group: Λ ·> wherein the atoms of said ring structure substituted at one or more positions may be a R ³ group. optionally A pharmaceutical composition according to claim, wherein R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ (R ³ ) ₂ , -OR ³ , -SR ³ , - NHCOR ³ , -N (R ³ ) 2, -CON (R ³ ) 2, -CONH (O) R ³ , -CONHNHSO ² R ³ , -COHNSO ² R ³ and -CONR ³ CN. • · Pharmaceutical composition according to claim 7, characterized in that the urea or carbamate of the N-heterocyclic carboxylic acid or the carboxylic acid isosteric compound is selected from the group consisting of compounds 1 to 151. A pharmaceutical composition according to claim 6, further comprising a neurotrophic factor different from the compound of formula (I). A pharmaceutical composition according to claim 12, wherein the neurotrophic factor other than the compound of formula (I) is selected from neurotropic growth factor, neuronal factor brain transfer, glial nerve transfer factor, ciliary neurotropic factor, insulin growth factor and active derivatives derived therefrom, acidic fibroblast growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5. 14. A method of treating a neurological disorder in an animal comprising: administering an animal an effective amount of urea or N-heterocyclic carboxylic acid or carboxylic acid isosteres to stimulate the growth of damaged peripheral nerves or to promote neuronal regeneration. 15. The method of claim 14, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical brain damage, spinal cord physical injury, stroke associated with brain damage, and neurodegeneration related neurological disorders. 16. The method of claim 14, wherein the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotropic lateral sclerosis. The method of claim 14, wherein the neurological disorder is Alzheimer's z 1 C X disease. The method of claim 14, wherein the neurological disorder is Parkinson's disease. 19. The method of claim 14, wherein the neurological disorder is amyotropic sclerosis. with e lateral 20. The method of claim 14, wherein the urea or carbamate of the N-heterocyclic carboxylic acid or carboxylic acid isoster is a non-immunosuppressive agent. A process according to claim 14, wherein the urea or carbamate of the N-heterocyclic carboxylic acid or the carboxylic acid isoster is a compound of formula (I): N k Wherein n is 1 to 3 R 1 and A are independently selected from the group consisting of hydrogen, C 1 -C 9 straight or branched chain alkyl, C, C 2 -C 9 straight or branched chain alkenyl, aryl, heteroaryl, carbocycle and heterocycle; D is a bond or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 straight or branched alkyl chain, C ₂ -C 6 straight or branched alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ , wherein R ⁴ is hydrogen or C 1 -C 9 straight or branched alkyl or alkenyl chain ; or a pharmaceutically acceptable salt, ester or solvate thereof. 22. The method according to claim 21, characterized in that R ₂ is a carbocycle or heterocycle containing any combination of _CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions with R ³ . 23. The method according to claim 21, characterized in that R ₂ is selected from the following group: Wherein the atoms of said ring structure substituted at one or more positions may be 1 or an R ³ group. The method of claim 21, wherein R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ (R ³ ) 2, -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2 , -CON (R ³⁾ 2, -CONH (O) R ^3, -CONHNHSO2R ³ -COHNSO2R ³ and -CONR ³ CN. · 25. The method of claim 14, wherein the urea or carbamate of the N-heterocyclic carboxylic acid or carboxylic acid isoster is selected from the group consisting of compounds 1 to 151. 26. The method of claim 14, further comprising administering neurotrophic factors other than the compound of formula (I). 27. The method of claim 26 wherein said neurotrophic factor different from the compound of formula (I) is selected from the group consisting of neurotrophic growth factor, brain growth factor, glial growth factor, ciliary neurotropic factor, insulin growth factor, and active zinc. derivatives derived therefrom, acidic fibroblast growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5. 28. A method of stimulating peripheral nerve growth comprising: administering an effective amount of an N-heterocyclic carboxylic acid urea or carbamate or carboxylic acid isosteres to the injured peripheral nerves to stimulate or promote the growth of the injured peripheral nerves. 29. The method of claim 28, wherein the urea or carbamate of the N-heterocyclic carboxylic acid or carboxylic acid isosteres is a non-immunosuppressive agent. A method according to claim 28, characterized in wherein n is 1 to 3 R 1 and A are independently selected from the group consisting of hydrogen, C ₁ -C ₉ straight or branched chain alkyl, C ₂ -C ₉ straight or branched chain alkenyl, aryl, heteroaryl, carbocycle and heterocycle; D is a bond or a C 1 -C 10 straight or branched alkyl chain, C ₂ -C 10 alkenyl or C ₂ -C 10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, groups: alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, akylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C ₆ straight or branched alkyl chain, C ₂ -C 6 straight or branched alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ wherein R ⁴ is hydrogen or C 1 - C ₆ A C9 straight or branched alkyl or ph alkenyl chain, or a pharmaceutically acceptable salt, ester or solvate thereof. The method of claim 30, wherein R ₂ is a carbocycle or heterocycle containing any combination of CH ₂ , O, S or N at any chemically stable oxidation stage, wherein any of the atoms of said ring structure are optionally substituted in one or more positions by group R ³ . 32. The method according to claim 30, characterized in that R ₂ is selected from the following group: fc Wherein the atoms of said ring structure may be optionally substituted at one or more positions by R ³ . The method of claim 30, wherein R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ NHR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ JR ³ is ₂ , -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2, -CON (R ³⁾ 2, -CONH (O) R ^3, -CONHNHSO2R ³ -COHNSO2R ³ and -CONR ³ CN. 34. The method of claim 28 wherein the urea or N-heterocyclic carboxylic acid carbamate; an acid or carboxylic acid isoster is a compound selected from the group consisting of compounds 1 to 151. 35. The method of claim 28, further comprising administering a neurotrophic factor different from the compound of formula (I). 36. The method of claim 35, wherein said neurotrophic factor different from the compound of formula (I) is selected from the group consisting of neurotrophic growth factor, brain growth factor, glial growth factor, ciliary neurotropic factor, insulin growth factor, and active agent. derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5. 37. A method of promoting neuronal regeneration and growth in an animal comprising: administering to the animal a therapeutically effective amount of a neurotropic urea or N-heterocyclic carboxylic acid or carboxylic acid isostere to promote neuronal regeneration. 38. The method of claim 37 wherein the urea or carbamate of the N-heterocyclic carboxylic acid or isosteric carboxylic acid is a non-immunosuppressive agent. 39. The method of claim 37, wherein the N-heterocyclic carboxylic acid or carboxylic acid isoster comprises a compound of formula (I): wherein * n is 1 to 3 R 1 and A are independently selected from the group consisting of hydrogen, C ₁ -C ₉ straight or branched chain alkyl, C ₂ -C ₉ straight or branched chain alkenyl, aryl, heteroaryl, carbocycle or heterocycle; • φ D is a bond or a C 1 -C 10 straight or branched alkyl chain, C ₂ -C 10 alkenyl or C ₂ -C 10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 direct or. a branched alkyl chain, a C ₂ -C 6 straight or branched alkenyl or alkynyl chain, an aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ , wherein R ⁴ is hydrogen or a C 1 -C 9 straight or branched alkyl or alkenyl chain, or a pharmaceutically acceptable a salt, ester or solvate. 40. The method according to claim 39, characterized in that R ₂ is a carbocycle or heterocycle containing any combination of _CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions with R ³ . 41. The method according to claim 39, characterized in that R ₂ is selected from the following group: X // HN — N COOH Him NH OH Y N — N o wherein the atoms of said ring structure may be optionally substituted at one or more positions by R ³ . 42. The method according to claim 39, characterized in that R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ (R ³ ) 2, -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2 , -CON (R ³⁾ _2, -CONH (O) R ^3, -CONHNHSO2R ³ -COHNSO2R ³ and -CONR ³ CN. 43. The method of claim 37, wherein the urea or N-heterocyclic carboxylic acid carbamate or carboxylic acid isosteric compound is selected from the group consisting of compounds 1 to 151. 'ϊ. 9999 • 9 99 9 9 9 9 9 ··· 9999 44. The method of claim 37, further comprising administering a neurotrophic factor different from the compound of formula (I). 45. The method of claim 44, wherein said neurotrophic factor different from the compound of formula (I) is selected from the group consisting of neurotrophic growth factor, brain growth factor, glial growth factor, ciliary neurotropic factor, insulin growth factor, insulin growth factor factor and active derivatives derived therefrom, acid fibroblast growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin 3 and neurotropin 4/5., 46. A method of preventing neurodegeneration in an animal, and tr on characterized in that it comprises: administering to ^the animal an effective amount of urea or carbamate of N-heterocyclic carboxylic acid or carboxylic acid isosteres preventing neurodegeneration. 47. The method of claim 46, wherein the neurodegeneration is Alzheimer's disease. 48. The method of claim 46, wherein the neurodegeneration is Parkinson's disease. 49. The method of claim 46, wherein the neurodegeneration is amyotrophic lateral sclerosis. A method according to claim 46, wherein the urea or N-heterocyclic carboxylic acid carbamate (i) 9 99 • ·· 0 9 9 0. 9 9 90 9999 99 * · r · 9 9 9 0 9 0 9 9 9 9 The acid or carboxylic acid isoster is a non-immunosuppressive agent. 51. The method of claim 46, wherein the urea or carbamate of the N-heterocyclic carboxylic acid or carboxylic acid isoster comprises a compound of formula (I): • (CH ₂ ) _n in which n rode to 3 R 1A are independently selected from the group consisting of hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isostere - ¹ ¼ of acid; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, groups: alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, akylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 straight or branched chain alkyl, C ₂ -C 6 straight or branched chain alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ , wherein R ⁴ is hydrogen or C 1 -C 9 straight or branched alkyl; an alkenyl chain, or a pharmaceutically acceptable salt, ester or solvate thereof. 52. The method according to claim 51, characterized in that R ₂ is a carbocycle or heterocycle containing any combination of _CH2, 0, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions by group R ³ . 53. The method according to claim 51, characterized in that R ₂ is selected from the following group: • · Ο wherein the atoms of said ring structure may optionally be substituted at one or more positions by R ³ . 54. The method according to claim 51, characterized in that R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, —PO ₃ (R ³ ) 2, -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2 , -CON (R ³⁾ _2, -CONH (O) R ^3, -CONHNHSO2R ³ -COHNSO2R ³ and -CONR ³ CN. 55. The process of claim 46, wherein the urea or N-heterocyclic carboxylic acid carbamate or carboxylic acid isostere compound is tc. _{v is} selected from the group consisting of compounds 1 to 151. , 'Fc 56. The method of claim 46, further comprising administering a neurotrophic factor different from the compound of formula (I). 57. The method of claim 56, wherein said neurotrophic factor different from the compound of formula (I) is selected from the group consisting of neurotrophic growth factor, brain growth factor, glial growth factor, ciliary neurotropic factor, insulin growth factor. factor, insulin growth factor and active derivatives thereof, acid fibroblast growth factor, basic fibroblast growth factor, platelet growth factor, neurotropin-3 and neurotropin 4/5. 58. A method of treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of urea or an N-heterocyclic carboxylic acid carbamate or carboxylic acid isosteres. 59. The method of claim 58, wherein the urea or N-heterocyclic carboxylic acid carbamate or carboxylic acid isoster is a non-immunosuppressive agent. The method of claim 58. characterized in that the urea or carbamate of the N-heterocyclic carboxylic acid or carboxylic acid isoster is a compound of formula (I): • (CH ₂ ) n in which n is 1 to 3, R 1 and A are independently selected from the group consisting of hydrogen, C 1 -C 8 straight or branched chain alkyl, C 2 -C 9 straight or ΡΛ, branched alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or isosteric carboxylic acid is optionally substituted with one or more substituents selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 straight or branched alkyl chain> C ₂ -C 6 straight or branched alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ wherein R ⁴ is hydrogen or C 1 -C 9 straight or branched alkyl or alkenyl chain or a pharmaceutically acceptable salt, ester or solvate thereof. 61. The method according to claim 60, characterized in that R ₂ is a carbocycle or heterocycle containing any combination of _CH2, 0, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions by group R ³ . 62. The method according to claim 60, characterized in that R ₂ is selected from the following group: ýf χ ? wherein the atoms of one or said ring structure may optionally be substituted by a plurality of R ³ groups. in 63. The method according to claim 60, characterized in that R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ³ , -PO 2 (R ³ ) 2, -CN, -PO ₃ (R ³ ) 2, -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2 , -CON (R ³⁾ _2, -CONH (O) R ^3, -CONHNHSO2R ³ -COHNSO2R -CONR ^3, and ^{R 3} is CN. < 64. The method of claim 58, wherein the carboxylic acid or carboxylic acid isostere ^of acid is selected from the group consisting of compounds 1 to 151st 65. A pharmaceutical composition comprising: (i) an effective amount of an N-heterocyclic carboxylic acid urea or carbamate or carboxylic acid isosteres for treating alopecia or promoting hair growth in animals, and (ii) a pharmaceutically acceptable carrier. 66. The method according to claim 65, ^{characterized,} in that ^the urea or carbamate of N-heterocyclic carboxylic acid or carboxylic acid isostere is non-immunosuppressive. i ·. 67. The method of claim 65, wherein the carboxylic acid or carboxylic acid isoster is a compound of formula (I): '0 ii r heteroaryl, the acid is a substituent in which n is 1 to 3, R 1 and A are independently selected from hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, aryl, heteroaryl, carbocycle or heterocycle; D is a bond or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R ₂ is a carboxylic acid or carboxylic acid isoster; wherein said alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle or carboxylic acid isoster optionally substituted with one or more selected from R ³ , wherein: R ³ is hydrogen, hydroxy, halogen, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkylo, mercapto, thioalkyl, alkylthio, sulfonylo; C 1 -C 6 straight or branched alkyl chain, C ₂ -C 6 straight or branched alkenyl or alkynyl chain, aryl, heteroaryl, carbocycle, heterocycle or CO ₂ R ⁴ , wherein R ⁴ is hydrogen or C 1 -C 9 straight or branched alkyl or alkenyl chain or a pharmaceutically acceptable salt, ester or solvate thereof. at. ζ 68. The method according to claim 67, characterized in that R ₂ is a carbocycle or heterocycle containing any combination * CH _2, O, S, or N in any chemically stable oxidation state, wherein any of the carbon Said ring structure are optionally substituted in one or multiple positions by group R ³ . .90 years Λ Φ · • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ 69. The method according to claim 67, characterized in that R ₂ is selected from the following group: wherein the atoms of said ring structure may be optionally substituted at one or more positions by R ³ . · 70. The composition according to claim 67, characterized in that R ₂ is selected from the group consisting of -COOH, -SO ₃ H, -SO ₂ HNR ^3, -PO2 ^(R3) 2, -CN, - PO ₃ (R ³ ) ₂ , -OR ³ , -SR ³ , -NHCOR ³ , -N (R ³ ) 2, -CON (R ³ ) 2, -CONH (O) R ³ , -CONHNHSO ² R ³ , -COHNSO ² R ³ and -CONR ³ CN. 71. The composition of claim 65, wherein the carboxylic acid or carboxylic acid isoster is selected from the group consisting of compounds 1 to 151.