US 2007 O161543A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0161543 A1 Yu et al. (43) Pub. Date: Jul. 12, 2007

(54) N-(PHOSPHONOALKYL)-AMINO ACIDS, (52) U.S. Cl...... 514/7: 514/114: 530/331; DERVATIVES THEREOF AND 558/170 COMPOSITIONS AND METHODS OF USE (76) Inventors: Ruey J. Yu, Chalfont, PA (US); Eugene J. Van Scott, Abington, PA (US) (57) ABSTRACT Correspondence Address: AKN GUMPSTRAUSS HAUER & FELD The present invention relates to an N-(phosphonoalkyl)- 6. COMMERCE SQUARE amino acid, a related compound or a derivative thereof, the 2005 MARKET STREET, SUITE 2200 N-(phosphonoalkyl)-amino acid, related compound or PHILADELPHIA, PA 19103 (US) derivative thereof being in a form as a free acid, salt, partial salt, lactone, amide or ester, or in Stereoisomeric or non (21) Appl. No.: 11/621,287 Stereoisomeric form, other than N-(phosphonomethyl)-gly (22) Filed: Jan. 9, 2007 cine or N.N-bis(phosphonomethyl)-glycine. Also included is a composition including an N-(phosphonoalkyl)-amino acid, Related U.S. Application Data a related compound or a derivative thereof in a form as a free (60) Provisional application No. 60/757,614, filed on Jan. acid, salt, partial salt, lactone, amide or ester, or in Stereoi 10, 2006. sy u. Is Someric or non-stereoisomeric form, and a cosmetically or pharmaceutically acceptable vehicle for topical or systemic Publication Classification administration to a mammalian Subject, as well as a method of administering an effective amount of Such a composition (51) Int. Cl. A6 IK 38/05 (2006.01) for alleviating or improving a condition, disorder, symptom A6 IK 3/66 (2006.01) or syndrome associated with at least one of a nervous, C07K 5/10 (2006.01) vascular, musculoskeletal or cutaneous system. US 2007/01 6 1543 A1 Jul. 12, 2007

N-(PHOSPHONOALKYL)-AMINO ACIDS, derivative thereof, the N-(phosphonoalkyl)-amino acid, DERVATIVES THEREOF AND COMPOSITIONS related compound or derivative thereof being in a form as a AND METHODS OF USE free acid, salt, partial salt, lactone, amide or ester, or in Stereoisomeric or non-stereoisomeric form, other than CROSS-REFERENCE TO RELATED N-(phosphonomethyl)-glycine or N.N-bis(phosphonom APPLICATIONS ethyl)-glycine. 0001) This application claims the benefit under 35 U.S.C. 0006 Another aspect of the present invention relates to S 119(e) of U.S. Provisional Application No. 60/757,614, an N-(phosphonoalkyl)-amino acid compound, a related filed Jan. 10, 2006, the entire disclosure of which is hereby compound or a compound derived therefrom, the compound incorporated herein by reference. includes the group consisting of N-(phosphonoalkyl)-pro line and a compound or derivative thereof having the BACKGROUND OF THE INVENTION following formula: 0002 The present invention relates to an N-(phospho noalkyl)-amino acid, a related compound or a derivative thereof, the N-(phosphonoalkyl)-amino acid, related com wherein R is H, an alkyl group having 1 to 19 carbon atoms, pound or derivative thereof being in a form as a free acid, an aryl group having 6 to 19 carbon atoms or an aralkyl salt, partial salt, lactone, amide or ester, or in Stereoisomeric group having 7 to 19 carbon atoms; and R can also carry or non-stereoisomeric form, other than N-(phosphonom OH, -SH, -SCH, -NH = NR,R, COR4, NH ethyl)-glycine or N,N-bis(phosphonomethyl)-glycine. The CONH, -NHC(=NR)NH, imidazole, pyrrolidine or present invention also relates to a composition including an other heterocyclic group; m is an integer from 0 to 5; R is N-(phosphonoalkyl)-amino acid, a related compound or a a phosphonoalkyl group having a formula derivative thereof in a form as a free acid, salt, partial salt, (HO)PO(CH), ; R is H or a phosphonoalkyl group lactone, amide or ester, or in Stereoisomeric or non-stereoi having a formula (HO)PO(CH), ; n is an integer from 1 Someric form, and a cosmetically or pharmaceutically to 9; R is —NH2 or —ORs. Rs is H, an alkyl group having acceptable vehicle for topical or systemic administration to 1 to 19 carbon atoms, an aryl group having 6 to 19 carbon a mammalian Subject, as well as a method of administering atoms or an aralkyl group having 7 to 19 carbon atoms; and an effective amount of Such a composition for alleviating or the H attached to any carbon atom can be substituted by I. improving a condition, disorder, symptom or syndrome F, Cl, Br, OH oran alkoxy group having 1 to 9 carbon atoms: associated with at least one of a nervous, vascular, muscu and wherein the N-(phosphonoalkyl)-amino acid, related loskeletal or cutaneous system. compound or derivative thereof is in a form as a free acid, salt, partial salt, lactone, amide or ester, or in a stereoiso 0003 N-(Phosphonomethyl)-glycine is listed as glypho meric or non-stereoisomeric form; provided that the com sate, CHNOP, molecular weight 169, in The Merck pound is not N-(phosphonomethyl)-glycine or N,N-bis(pho Index, 13" edition, 2001, page 803. The mono(isopropy sphonomethyl)-glycine. lamine) salt of N-(phosphonomethyl)-glycine is a primary active ingredient in Roundup(R) herbicide. N,N-Bis(pho 0007 Another aspect of the present invention relates to a sphonomethyl)-glycine is listed as glyphosine, composition comprising an N-(phosphonoalkyl)-amino CH, NO,P, molecular weight 263, in The Merck Index, acid, a related compound or a derivative thereof, the 13 edition, 2001, page 804. This compound is listed as plant N-(phosphonoalkyl)-amino acid, related compound or growth regulator known to cause chlorosis in green plants, derivative thereof being in a form as a free acid, salt, partial and also used as a chemical ripener. U.S. Pat. No. 3,288,846 salt, lactone, amide or ester, or in Stereoisomeric or non entitled “Processes for Preparing Organo-Phosphonic Stereoisomeric form, and a cosmetically or pharmaceutically Acids' describes a synthesis of N-substituted aminometh acceptable vehicle for topical or systemic administration to ylenephosphonic acid. U.S. Pat. No. 3,799,758 entitled a mammalian Subject. “N-Phosphonomethyl-Glycine Phytotoxicant Composi 0008. Yet another aspect of the present invention relates tions' describes N-(phosphonomethyl)-glycine and its to a method of alleviating or improving a condition, disor derivatives useful as phytotoxicants and herbicides. U.S. der, symptom or syndrome associated with at least one of a Pat. No. 3,853,530 entitled “Regulating Plants with nervous, vascular, musculoskeletal or cutaneous system, the N-phosphonomethyl-Glycine and Derivatives Thereof method comprising administering to a mammalian Subject describes the use of N-Phosphonomethyl-glycine and having the disorder, symptom or syndrome an amount derivatives useful for regulating the natural growth and effective for alleviating or improving the condition, disorder, development of plants. symptom or syndrome of a composition comprising an 0004 There has been no teaching, suggestion or impli N-(phosphonoalkyl)-amino acid, a related compound or a cation about the use of N-(phosphonomethyl)-glycine or its derivative thereof, the N-(phosphonoalkyl)-amino acid, derivatives for topical or systemic administration to mam related compound or derivative thereof being in a form as a mals, including humans. The present inventors have deter free acid, salt, partial salt, lactone, amide or ester, or in mined that such compounds are useful for treating various Stereoisomeric or non-stereoisomeric form, and a cosmeti medical and cosmetic conditions in animals, such as mam cally or pharmaceutically acceptable vehicle for topical or mals, and including humans. systemic administration to the mammalian Subject. 0009. The cosmetic conditions and medical disorders, BRIEF SUMMARY OF THE INVENTION symptoms or syndromes associated with at least one of a 0005 One aspect of the present invention relates to an nervous, vascular, musculoskeletal or cutaneous system, and N-(phosphonoalkyl)-amino acid, a related compound or a others, include, by way of example and not limitation, itch, US 2007/01 6 1543 A1 Jul. 12, 2007

pain, inflammation, erythema, eczema, dermatitis, derma N-(phosphonomethyl)-amino acids can be formed including toses, arthritis, acne, rosacea, dry skin, ichthyosis, keratoses, different stereoisomers such as D. L. and DL forms. psoriasis, pigmented skin, aging related skin changes. The 0017 Some amino acids are metabolites or are related to compositions may also be used for skin lightening. or derived from the common amino acids. Other amino acids 0010. As used herein, the singular forms an’, and have amino group(s) at other positions of the carbon chain, “the include plural referents unless the context clearly such as the B or Y position. Still other amino acids are found dictates otherwise. Thus, for example, reference to “a com in nature produced by microorganisms or plants. Certain pound” includes a plurality of Such compounds. amino acids, such as taurine, can have a Sulfonic acid group instead of a carboxyl group. Peptides are derived from DETAILED DESCRIPTION OF THE amino acids, and the peptides are called related amino acids INVENTION or amino acid derivatives. Other organic compounds which have at least one carboxyl group and at least one alkaline 0011. As noted above, the present invention relates to an group Such as amino, imino or guanidino group are also N-(phosphonoalkyl)-amino acid, a related compound or a called “related amino acids. As used herein, all these derivative thereof, the N-(phosphonoalkyl)-amino acid, compounds are called related amino acids. Representative, related compound or derivative thereof being in a form as a but non-limiting related amino acids include: B-alanine, free acid, salt, partial salt, lactone, amide or ester, or in y-aminobutanoic acid, B-aminoisobutanoic acid, anserine, Stereoisomeric or non-stereoisomeric form, other than aminolevulinic acid, camosine, canaline, canavanine, citrul N-(phosphonomethyl)-glycine or N.N-bis(phosphonom line, creatine, creatinine, cysteine Sulfinic acid, cystine, ethyl)-glycine. cycloserine, dopa (3,4-dihydroxyphenylalanine), dopamine (hydroxytyramine), ethionine, glutathione, guanidinoacetic 0012 Typical, but non-limiting phosphonoalkyl groups acid, homocarnosine, homocysteine, homoserine, 4-hydrox include phosphonomethyl, phosphonoethyl, phosphonopro yphenylglycine, hydroxyglutamic acid, hydroxylysine, pyl, phosphonoisopropyl, phosphonobutyl, phospho hydroxyproline, hypusine, homoarginine, homocitrulline, noisobutyl, phosphonopentyl, phosphonoisopentyl, homocystine, homophenylalanine, homotryptophan, phosphonooctyl and phosphonoisooctyl groups. hydroxylysine, hydroxyarginine, hydroxyhomoarginine, 0013 The present invention also relates to a composition hydroxycitrulline, hydroxyornithine, hydroxyvaline, including an N-(phosphonoalkyl)-amino acid, a related com indospicine, methoxinine, methylarginine, methylhistidine, pound or a derivative thereof in a form as a free acid, salt, methyllysine, methylomithine, methylserine, norvaline, partial salt, lactone, amide or ester, or in Stereoisomeric or omithine, oxalysine, penicillamine (dimethylcysteine), phe non-stereoisomeric form, and a cosmetically or pharmaceu nylglycine, 3-phenylserine, sarcosine (N-methylglycine), tically acceptable vehicle for topical or systemic adminis serotonin (hydroxytryptamine), taurine, tryptamine and tration to a mammalian Subject. The composition includes tyramine. N-(phosphonoalkyl)-glycine, its related compounds and 0018. As used herein, the N-(phosphonoalkyl) or prefer derivatives thereof, since they are not known for use in ably the N-(phosphonomethyl) derivatives of the amino treating mammals, including humans. acids as described in paragraphs 0016 and 0017 above, 0014. The present invention additionally relates to a and certain others described elsewhere herein, are called method of administering an effective amount of Such a “N-(phosphonoalkyl)-related amino acids.” preferably composition for alleviating or improving a condition, dis “N-(phosphonomethyl)-related amino acids, or simply order, symptom or syndrome associated with at least one of “related compounds” (or other similar grammatical terms). a nervous, vascular, musculoskeletal or cutaneous system, or The "derivatives thereof (or other similar grammatical others. forms) represent all other compounds which are chemically derived from the N-(phosphonoalkyl)-amino acids, the 0.015 The compositions comprising N-(phospho N-(phosphonoalkyl)-related amino acids, and preferably noalkyl)-amino acids, preferably N-(phosphonomethyl)- N-(phosphonomethyl)-amino acids and N-(phosphonom amino acids, related compounds or derivatives thereof, and ethyl)-related amino acids. their topical or systemic administration to animals, such as 0019 Conditions, disorders, symptoms and syndromes mammals, including humans, are believed to be beneficial or associated with the (A) nervous, (B) vascular, (C) mascu therapeutically effective for cosmetic conditions or medical loskeletal, (D) cutaneous system, and others that may be disorders associated with nervous, vascular, masculoskel treated with a composition of the present invention can be etal, or cutaneous systems, or others. described as follows. 0016. The amino acid as used herein represents as a broad definition an organic compound which has at least one 0020 (A) Nervous System. carboxyl group and at least one alkaline group such as 0021. Throughout this description, the conditions, disor amino, imino or guanidino group. The common amino acids ders, symptoms and syndromes associated with the nervous represent twenty amino acids which have an amino group at system include the following conditions or disorders, which the alpha position of the carbon chain and are present in may present as indicated, or otherwise: (1) dementia and proteins. These common amino acids are alanine, arginine, Alzheimer's disease: progressive loss of memory, shrinkage aspartic acid, asparagine, cysteine, glycine, glutamic acid, and atrophy of cerebral cortex, tangles of fibers in nerve glutamine, histidine, isoleucine, leucine, lysine, methionine, cells, senile plaques of amyloid, decreased choline acetyl phenylalanine, proline, serine, threonine, tryptophan, transferase enzyme; (2) carpal tunnel syndrome: weakness, tyrosine and Valine. From these common amino acids, pain, tingling, numbness, burning in palm and fingers; (3) twenty N-(phosphonoalkyl)-amino acids, preferably twenty encephalitis: inflammation of the brain; (4) headache: US 2007/01 6 1543 A1 Jul. 12, 2007 migraine, expansion of blood vessels pressing on nerves or collagen, glycosaminoglycans, proteoglycans and elastin, as constriction blocking blood Supply, inflammation, muscle well as diminished levels of such components in the dermis; contraction to face, neck or scalp; (5) meningitis: infection uneven skin tone; uneven and rough surface of skin, nail and of spinal fluid and meninges; (6) neuralgia: nerve pain, hair, loss or reduction of skin, nail and hair resiliency, peripheral neuropathy, sciatica, shingles, trigeminal neural elasticity and recoilability: laxity; lack of skin, nail and hair gia; (7) Parkinson's disease: tremors in limbs, muscular lubricants and luster, fragility and splitting of nail and hair; rigidity; (8) amnesia: loss of memory and inability to form yellowing skin; reactive, irritating or telangiectatic skin; and new memory; and (9) others, such as ataxia, Bell's palsy, dull and older-looking skin, nail and hair. In addition, epilepsy, multiple Sclerosis, myasthenia gravis, narcolepsy, N-(phosphonoalkyl)-amino acids can be used for general paralysis and rabies. care of skin, nail and hair, to improve skin texture and pores, flakiness and redness; to make skin Soft, Smooth, fresh, 0022 (B) Vascular System. balanced, visibly clear, even-toned and brighter, to increase 0023 Throughout this description, vascular conditions, skin fullness and plumpness; and for skin bleach and light reactions and disorders that may be treated with a compo ening and wound healing. sition of the present invention include acanthosis nigricans, 0028 Skin, nail and hair infections can be caused by acrocyanosis, actinic cheilitis, actinic prurigo, dermatitis, microorganisms which include bacteria, fungi, yeasts, dermatosis, dermographism, dyshidrosis, drug eruptions, molds, parasites and viruses. More specifically, the bacterial eczema, erythema, erythema migrans, erythrocyanosis, infections can cause trichomycosis axillaris, pitted keratoly erythromelalgia, familial hemorrhage, histamine reaction, sis, erythrasma, impetigo, ecthyma, furunculosis (boils), inflammatory papular and pustular lesions, lichen planus, carbuncle, Scalded skin syndrome, toxic shock syndrome, lupus erythematosus, mycosis fungoides, neurodermatitis, erysipelas, cellulitis, necrotizing fasciitis, erysipeloid, cat neuropeptide and neurovascular reactions, parapsoriasis, scratch disease (Rochalinaea hemselae), syphilis, lyme dis perniosis (chilblains), photoallergy, photoreaction, photo ease (Borrelia burgdorferi), cutaneous anthrax (Bacillus sensitivity, pityriasis rosea, pityriasis rubra pilaris, polymor anthracis), gonococcal septicaemia, inoculation tuberculo phic light eruption, psoriasis, rhinophyma, rosacea, Sclero sis, scrofuloderma, tuberculides, erythema induratum, lep sis, spider naevi, T-cell disorders, telangiectasia, urticaria rosy (Mycobacterium leprae), mycobacterium ulcerans, and other vascular reactions. leishmaniasis and acute paronychia. The viral infections can 0024 (C) Musculoskeletal System. cause viral warts (human papilloma virus), varicella (chick enpox), herpes Zoster (varicella-Zoster), herpes simplex (her 0.025 The conditions or abnormalities of musculoskeletal pesvirus hominis), molluscum contagiosum, orf, AIDS system include the following conditions or disorders, which (acquired immunodeficiency syndrome, human immunode may present as indicated, or otherwise: (1) osteoporosis: ficiency virus, HIV), herpangina, mucocutaneous lymph reduction of calcium in bone leading to thin bone and bone node syndrome (Kawasaki's disease), Gianotti-Crosti Syn susceptible to fracture; (2) osteoarthritis: inflammation of drome (hepatitis B virus), measles, rubella and erythema joint cartilage provoking Swelling and pain; (3) rheumatoid infectiosum. The fungal infections can cause ringworm, arthritis: inflammation of synovium and destruction of car tinea pedis (athlete's foot), tinea nails, tinea hands, tinea tilage, damage to heart, lungs, nerves and eyes; (4) anky groin, tinea trunk and limbs, tinea capitis (Scalp), oral losing spondylitis: arthritis affecting Sacroiliac joints and candidiasis, candida intertrigo, genital candidiasis, chronic spine with inflammation and immovability; (5) bursitis: paronychia, chronic mucocutaneous candidiasis, pityriasis inflammation of bursa; (6) tendinitis: inflammation of ten versicolor, histoplasmosis, coccidioidomycosis, blastomy don; (7) gout: recurrent acute arthritis from uric acid deposit; cosis, sporotrichosis, actinomycosis and mycetoma (madura and (8) others, such as backache, bunion and hernia. foot). 0026 (D) Cutaneous System, and Others. 0029. The systemic administration includes parenteral 0027. The cosmetic, dermatological or other conditions injection, Such as intravenous or intraarterial injection or and disorders of cutaneous system that my be treated with a infusion, Subcutaneous, intramuscular or other injection, as composition of the present invention include deranged or well as oral, transdermal and other routes. The preferred disordered cutaneous or mucocutaneous tissue relevant to systemic administration is oral administration. skin, nail and hair, oral, vaginal and anal mucosa; disturbed 0030 Certain N-(phosphonoalkyl)-amino acids, related keratinization; inflammation; changes associated with intrin compounds and derivatives thereof can be represented by sic and extrinsic aging, and others which may or may not be the following generic formula: related to cutaneous system. The manifestations include acne; rosacea; age spots; blemished skin; blotches; cellulite; dermatoses; dermatitis; skin, nail and hair infections; dan wherein R is H, an alkyl group having 1 to 19 carbon atoms, druff dryness or looseness of skin, nail and hair, Xerosis: an aryl group having 6 to 19 carbon atoms or an aralkyl eczema: elastosis; herpes; hyperkeratosis; hyperpigmented group having 7 to 19 carbon atoms; and R can also carry skin; ichthyosis; keratoses; lentigines; melasmas; mottled OH, -SH, -SCH, -NH, -NRR, COR - NH skin; pseudofolliculitis barbae; photoaging and photodam CONH, -NHC(=NR)NH, imidazole, pyrrolidine or age; pruritus; psoriasis; skin lines; stretch marks; thinning of other heterocyclic group; m is an integer from 0 to 5; R is skin, nail plate and hair, warts; wrinkles; oral or gum a phosphonoalkyl group having a formula disease; irritated, inflamed, red, unhealthy, damaged or (HO)PO(CH), ; R is H or a phosphonoalkyl group abnormal mucosa, skin, hair, nail, nostril, ear canal, anal or having a formula (HO)PO(CH), ; n is an integer from 1 vaginal conditions; breakdown, defective synthesis or repair to 9; R is —NH2 or —ORs. Rs is H, an alkyl group having of dermal components; abnormal or diminished synthesis of 1 to 19 carbon atoms, an aryl group having 6 to 19 carbon US 2007/01 6 1543 A1 Jul. 12, 2007 atoms or an aralkyl group having 7 to 19 carbon atoms; and N-(phosphonoalkyl)-glycine, N-(phosphonoalkyl)-glutamic the H attached to any carbon atom can be substituted by I. acid, N-(phosphonoalkyl)-glutamine, N-(phosphonoalkyl)- F, Cl, Br, OH or an alkoxy group having 1 to 9 carbonatoms. histidine, N-(phosphonoalkyl)-isoleucine, N-(phospho Typical, but non-limiting phosphonoalkyl groups include noalkyl)-leucine, N-(phosphonoalkyl)-lysine, N-(phospho phosphonomethyl, phosphonoethyl, phosphonopropyl. noalkyl)-methionine, N-(phosphonoalkyl)-phenylalanine, phosphonoisopropyl, phosphonobutyl, phosphonoisobutyl, N-(phosphonoalkyl)-proline, N-(phosphonoalkyl)-serine, phosphonopentyl, phosphonoisopentyl, phosphonooctyl and N-(phosphonoalkyl)-threonine, N-(phosphonoalkyl)-tryp phosphonoisooctyl groups. The most preferred one is tophan, N-(phosphonoalkyl)-tyrosine and N-(phospho phosphonomethyl group. The N-(phosphonoalkyl)-amino noalkyl)-valine. acid, related compound or derivative thereof can be present in a form as free acid, salt or partial salt with organic or 0036 Representative, non-limiting mono-substituted inorganic alkali, amide, ester or lactone, as a stereoisomer related amino acids include: Such as in D. L., or DL form, or as a non-stereoisomer Such 0037 N-(phosphonoalkyl)-3-alanine, N-(phospho as N-(phosphonoalkyl)-p-alanine. Among N-(phospho noalkyl)-y-aminobutanoic acid, N-(phosphonoalkyl)-3-ami noalkyl)-amino acids, N-(phosphonoalkyl)-proline cannot noisobutanoic acid, N-(phosphonoalkyl)-anserine, be represented by the above generic structure because the N-(phosphonoalkyl)-aminolevulinic acid, N-(phospho a-amino group is part of the heterocyclic pyrrolidine ring. noalkyl)-camosine, N-(phosphonoalkyl)-canaline, Therefore, N-(phosphonoalkyl) derivatives of proline such N-(phosphonoalkyl)-canavanine, N-(phosphonoalkyl)-cit as N-(phosphonoalkyl)-proline, N-(phosphonoalkyl)-proli rulline, N-(phosphonoalkyl)-creatine, N-(phosphonoalkyl)- namide and N-(phosphonoalkyl)-proline esters will be rep creatinine, N-(phosphonoalkyl)-cysteine Sulfinic acid, resented by their chemical names. In the same manner, N-(phosphonoalkyl)-cystine, N-(phosphonoalkyl)-cyclos chemical names will be used if other compounds of the erine, N-(phosphonoalkyl)-dopaN-(phosphonoalkyl)-3,4- present invention cannot be covered by the above generic dihydroxyphenylalanine), N-(phosphonoalkyl)-dopamine Structure. (hydroxytyramine), N-(phosphonoalkyl)-ethionine, 0031 Each of the amino groups of an amino acid exclud N-(phosphonoalkyl)-glutathione, N-(phosphonoalkyl)- ing proline has two hydrogen atoms attached to the nitrogen guanidinoacetic acid, N-(phosphonoalkyl)-3-guanidinopro atom, and can form a bis or di(phosphonoalkyl)-amino acid panoic acid, N-(phosphonoalkyl)-4-guanidinobutanoic acid, such as N,N-bis(phosphonoalkyl)-alanine and N,N-bis(pho N-(phosphonoalkyl)-homocarnosine, N-(phosphonoalkyl)- sphonoalkyl)-tyrosine. homocysteine, N-(phosphonoalkyl)-homoserine, N-(phosphonoalkyl)-4-hydroxyphenylglycine, N-(phospho 0032 Most amino acids and related amino acids have noalkyl)-hydroxyglutamic acid, N-(phosphonoalkyl)-hy only one amino group attached to the alpha or other position droxylysine, N-(phosphonoalkyl)-hydroxyproline, of the carbon atom, and can have only one or two (phospho N-(phosphonoalkyl)-hypusine, N-(phosphonoalkyl)-ho noalkyl) groups attached to the amino group Such as moarginine, N-(phosphonoalkyl)-homocitrulline, N-(phosphonoalkyl)-serine and N,N-bis(phosphonoalkyl)- N-(phosphonoalkyl)-homocystine, N-(phosphonoalkyl)-ho serine. Some amino acids and related amino acids, such as mophenylalanine, N-(phosphonoalkyl)-homotryptophan, lysine, omithine, arginine, histidine and tryptophan have N-(phosphonoalkyl)-hydroxylysine, N-(phosphonoalkyl)- additional amino, imino or guanidino groups in addition to hydroxyarginine, N-(phosphonoalkyl)-hydroxyhomoargin the alpha amino group, and can form one to four (phospho ine, N-(phosphonoalkyl)-hydroxycitrulline, N-(phospho noalkyl) groups, for example: N-(phosphonoalkyl)-amino noalkyl)-hydroxyornithine, N-(phosphonoalkyl)- acids: N'-(phosphonoalkyl)-amino acids; N,N-bis(phospho hydroxyvaline, (phosphonoalkyl)-iminodiacetic acid, noalkyl)-amino acids; N,N'-bis(phosphonoalkyl)-amino N-(phosphonoalkyl)-indospicine, N-(phosphonoalkyl)- acids: N',N'-bis(phosphonoalkyl)-amino acids; N.N.N'-tris methoxinine, N-(phosphonoalkyl)-methylarginine, (phosphonoalkyl)-amino acids: N,N',N'-tris(phospho N-(phosphonoalkyl)-methylhistidine, N-(phosphonoalkyl)- noalkyl)-amino acids and N.N.N',N'-tetra(phosphonoalkyl)- methyllysine, N-(phosphonoalkyl)-methylomithine, amino acids. Non-limiting examples a N-(phosphonoalkyl)-methylserine, N-(phosphonoalkyl)- N-(phosphonoalkyl)-lysine; N'-(phosphonoalkyl)-lysine; norvaline, N-(phosphonoalkyl)-omithine, N-(phospho N,N-bis(phosphonoalkyl)-lysine; N,N'-bis(phospho noalkyl)-oxalysine, N-(phosphonoalkyl)-penicillamine noalkyl)-lysine; N',N'-bis(phosphonoalkyl)-lysine; N.N.N'- (N-phosphonoalkyl-dimethylcysteine), N-(phospho tris(phosphonoalkyl)-lysine; N.N',N'-tris(phosphonoalkyl)- noalkyl)-phenylglycine, N-(phosphonoalkyl)-3-phe lysine and N.N.N',N'-tetra(phosphonoalkyl)-lysine. All of nylserine, N-(phosphonoalkyl)-sarcosine (N-phospho the foregoing are to be included as “related compounds” or noalkyl-N-methyl-glycine), N-(phosphonoalkyl)-serotonin “derivatives. (N-phosphonoalkyl-hydroxytryptamine), N-(phospho 0033. A more preferred N-(phosphonoalkyl) compound noalkyl)-taurine, N-(phosphonoalkyl)-tryptamine and has a single phosphonoalkyl radical attached to an amino N-(phosphonoalkyl)-tyramine. group of an amino acid or related amino acid, Such as alpha 0038 Representative, non-limiting di- or bis-substituted N-(phosphonoalkyl)-lysine and N-(phosphonoalkyl)-y-ami amino acids include: nobutanoic acid. 0039 N,N-bis(phosphonoalkyl)-alanine; N.N-bis(pho 0034 Representative non-limiting mono-substituted sphonoalkyl)-arginine; N,N-bis(phosphonoalkyl)-aspar common amino acids include: agine; N.N-bis(phosphonoalkyl)-aspartic acid: N,N-bis 0035 N-(phosphonoalkyl)-alanine, N-(phosphonoalkyl)- (phosphonoalkyl)-cysteine; N,N-bis(phosphonoalkyl)- arginine, N-(phosphonoalkyl)-asparagine, N-(phospho glycine; N.N-bis(phosphonoalkyl)-glutamic acid; N.N- noalkyl)-aspartic acid, N-(phosphonoalkyl)-cysteine, bis(phosphonoalkyl)-glutamine; N.N-bis(phosphonoalkyl)- US 2007/01 6 1543 A1 Jul. 12, 2007 histidine; N.N-bis(phosphonoalkyl)-isoleucine; N.N- noalkyl)-tyramine. These di- or bis-substituted related bis(phosphonoalkyl)-leucine; N.N-bis(phosphonoalkyl)- amino acids are included with the invention as derivatives of lysine; N,N-bis(phosphonoalkyl)-methionine: N,N- related amino acids. bis(phosphonoalkyl)-phenylalanine; N,N- bis(phosphonoalkyl)-serine; N,N-bis(phosphonoalkyl)- 0042 Any of the above phosphonoalkyl-amino acids, threonine; N.N-bis(phosphonoalkyl)-tryptophan; N.N- related compounds and derivatives thereof can be present as bis(phosphonoalkyl)-tyrosine; N.N-bis(phosphonoalkyl)- a free acid, Salt or partial salt with organic or inorganic valine; N,N'-bis(phosphonoalkyl)-arginine: N,N'- alkali, lactone, amide, ester or in Stereoisomeric or non bis(phosphonoalkyl)-histidine; N.N'-bis(phosphonoalkyl)- Stereoisomeric form. lysine; N,N'-bis(phosphonoalkyl)-tryptophan. These di- or 0043. As an illustration, N-(phosphonoalkyl)-proline bis-Substituted amino acids are within the category of includes for example, N-(phosphonoalkyl)-L-proline; derivatives of amino acids. N-(phosphonoalkyl)-L-proline Sodium salt; N-(phospho noalkyl)-L-prolinamide, N-(phosphonoalkyl)-L-proline 0040 Representative non-limiting di- or bis-substituted methyl ester, N-(phosphonoalkyl)-L-proline ethyl ester, related amino acids and derivatives include: N-(phosphonoalkyl)-L-proline propyl ester and 0041 N,N-bis(phosphonoalkyl)-3-alanine; N.N-bis(pho N-(phosphonoalkyl)-L-proline isopropyl ester. sphonoalkyl)-y-aminobutanoic acid; N,N-bis(phospho 0044) The preferred phosphonoalkyl groups are phospho noalkyl)-3-aminoisobutanoic acid: N,N-bis(phospho nomethyl, phosphonoethyl, phosphonopropyl, phospho noalkyl)-anserine; N,N-bis(phosphonoalkyl)- noisopropyl, phosphonobutyl, phosphonoisobutyl, phospho aminolevulinic acid, N.N-bis(phosphonoalkyl)-carnosine; nopentyl, phosphonoisopentyl, phosphonooctyl and N,N-bis(phosphonoalkyl)-canaline; N,N-bis(phospho phosphonoisooctyl groups. Therefore, the preferred com noalkyl)-canavanine; N.N-bis(phosphonoalkyl)-citrulline; pounds of the present invention are N-(phosphonomethyl)- N,N-bis(phosphonoalkyl)-creatine; N,N-bis(phospho amino acids, N-(phosphonoethyl)-amino acids, N-(phospho noalkyl)-creatinine; N,N-bis(phosphonoalkyl)-cysteine nopropyl)-amino acids, N-(phosphonoisopropyl)-amino sulfinic acid; N,N-bis(phosphonoalkyl)-cystine; N.N-bis acids, N-(phosphonobutyl)-amino acids, N-(phospho (phosphonoalkyl)-cycloserine; N,N-bis(phosphonoalkyl)- noisobutyl)-amino acids, N-(phosphonopentyl)-amino dopaN,N-bis(phosphonoalkyl)-3,4-dihydroxyphenylala acids, N-(phosphonoisopentyl)-amino acids, N-(phospho nine: N,N-bis(phosphonoalkyl)-dopamine nooctyl)-amino acids, N-(phosphonoisooctyl)-amino acids, (hydroxytyramine); N,N-bis(phosphonoalkyl)-ethionine: and the related amino acid compounds and derivatives N,N-bis(phosphonoalkyl)-glutathione; N.N-bis(phospho thereof. noalkyl)-guanidinoacetic acid, N.N-bis(phosphonoalkyl)-3- guanidinopropanoic acid; N,N-bis(phosphonoalkyl)-4- 0045. The most preferred compounds are N-(phospho guanidinobutanoic acid; N,N-bis(phosphonoalkyl)- nomethyl)-amino acids, related compounds and derivatives homocamosine; N.N-bis(phosphonoalkyl)-homocysteine; thereof, in which R is a (phosphonomethyl) group having N,N-bis(phosphonoalkyl)-homoserine; N.N-bis(phospho the formula (HO)PO(CH), and R is H or a phosphonom noalkyl)-4-hydroxyphenylglycine; N,N-bis(phospho ethyl group having the formula (HO),PO(CH) in the above noalkyl)-hydroxyglutamic acid; N,N-bis(phosphonoalkyl)- generic structure. hydroxylysine; N.N-bis(phosphonoalkyl)-hydroxyproline; N,N-bis(phosphonoalkyl)-hypusine; N,N-bis(phospho 0046 Among N-(phosphonomethyl)-amino acids, noalkyl)-homoarginine; N.N-bis(phosphonoalkyl)-homoc N-(phosphonomethyl)-proline cannot be represented by the itrulline; N.N-bis(phosphonoalkyl)-homocystine; N.N-bis above generic structure because the alpha amino group is (phosphonoalkyl)-homophenylalanine; part of the heterocyclic pyrrolidine ring. Therefore, bis(phosphonoalkyl)-homotryptophan; N-(phosphonomethyl) derivatives of proline such as bis(phosphonoalkyl)-hydroxylysine; N-(phosphonomethyl)-proline, N-(phosphonomethyl)-proli bis(phosphonoalkyl)-hydroxyarginine; namide and N-(phosphonomethyl)-proline esters will be bis(phosphonoalkyl)-hydroxyhomoarginine; represented by their chemical names. In the same manner, bis(phosphonoalkyl)-hydroxycitrulline; chemical names will be used if other compounds of the bis(phosphonoalkyl)-hydroxyomithine; present invention cannot be covered by the above generic bis(phosphonoalkyl)-hydroxyvaline; Structure. bis(phosphonoalkyl)-indospicine; 0047 As aforementioned, each of any of the amino bis(phosphonoalkyl)-methoxinine; groups of an amino acid excluding proline has two hydrogen bis(phosphonoalkyl)-methylarginine; atoms attached to the nitrogen atom, and can form bis- or bis(phosphonoalkyl)-methylhistidine: di-(phosphonomethyl)-amino acid such as N,N-bis(pho bis(phosphonoalkyl)-methyllysine; sphonomethyl)-cysteine and N,N-bis(phosphonomethyl)- bis(phosphonoalkyl)-methylomithine; leucine. Mostamino acids and related amino acids have only bis(phosphonoalkyl)-methylserine; one amino group attached to the alpha or other position of bis(phosphonoalkyl)-norvaline; N.N-bis(phosphonoalkyl)-ky the carbon atom, and can have only one or two (phospho omithine; N.N-bis(phosphonoalkyl)-oxalysine; N.N- nomethyl) groups attached to the amino group such as bis(phosphonoalkyl)-penicillamine (N-phosphonoalkyl N-(phosphonomethyl)-serine and N,N-bis(phosphonom dimethylcysteine); N,N-bis(phosphonoalkyl)- ethyl)-serine. Some amino acids and related amino acids, phenylglycine; N.N-bis(phosphonoalkyl)-3-phenylserine; Such as lysine, omithine, arginine, histidine and tryptophan N,N-bis(phosphonoalkyl)-serotonin (N-phosphonoalkyl-hy have additional amino, imino or guanidino group in addition droxytryptamine); N,N-bis(phosphonoalkyl)-taurine; N.N- to the alpha amino group, and can form one to four bis(phosphonoalkyl)-tryptamine and N,N-bis(phospho (phosphonomethyl) groups, such as N-(phosphonomethyl)- US 2007/01 6 1543 A1 Jul. 12, 2007 amino acids: N'-(phosphonomethyl)-amino acids; N,N-bis hydroxycitrulline, N-(phosphonomethyl)-hydroxyomithine, (phosphonomethyl)-amino acids; N,N'-bis(phosphonom N-(phosphonomethyl)-hydroxyvaline, N-(phosphonometh ethyl)-amino acids; N'N'-bis(phosphonomethyl)-amino yl)iminodiacetic acid, N-(phosphonomethyl)-indospicine, acids: N.N.N'-tris(phosphonomethyl)-amino acids: N,N',N'- N-(phosphonomethyl)-methoxinine, N-(phosphonomethyl)- tris(phosphonomethyl)-amino acids and N.N.N'N'-tetra methylarginine, N-(phosphonomethyl)-methylhistidine, (phosphonomethyl)-amino acids. Non-limiting examples are N-(phosphonomethyl)-methyllysine, N-(phosphonom N-(phosphonomethyl)-lysine: N'-(phosphonomethyl)- ethyl)-methylomithine, N-(phosphonomethyl)-meth lysine; N.N-bis(phosphonomethyl)-lysine; N.N'-bis(pho ylserine, N-(phosphonomethyl)-norvaline, N-(phosphonom sphonomethyl)-lysine; N',N'-bis(phosphonomethyl)-lysine; ethyl)-omithine, N-(phosphonomethyl)-oxalysine, N.N.N'-tris(phosphonomethyl)-lysine; N.N'N'-tris(phospho N-(phosphonomethyl)-penicillamine (N-phosphonomethyl nomethyl)-lysine and N.N.N'N'-tetra(phosphonomethyl)- dimethylcysteine), N-(phosphonomethyl)-phenylglycine, lysine. A presently more preferred N-(phosphonomethyl) N-(phosphonomethyl)-3-phenylserine, N-(phosphonom derivative is a single phosphonomethyl radical attached to ethyl)-sarcosine (N-phosphonomethyl-N-methyl-glycine), an amino group of an amino acid or related amino acid. Such N-(phosphonomethyl)-serotonin (N-phosphonomethyl-hy as alpha N-(phosphonomethyl)-lysine and N-(phosphonom droxytryptamine), N-(phosphonomethyl)-taurine, ethyl)-y-aminobutanoic acid. N-(phosphonomethyl)-tryptamine and N-(phosphonom ethyl)-tyramine. These compounds are within the category 0.048. The preferred mono-substituted common amino of N-(phosphonomethyl)-related amino acids, or simply, acids include: related compounds. 0049 N-(phosphonomethyl)-alanine, N-(phosphonom ethyl)-arginine, N-(phosphonomethyl)-asparagine, 0052 The preferred di- or bis-substituted common amino N-(phosphonomethyl)-aspartic acid, N-(phosphonomethyl)- acids are: cysteine, N-(phosphonomethyl)-glycine, N-(phosphonom 0053 N.N-bis(phosphonomethyl)-alanine; N.N-bis(pho ethyl)-glutamic acid, N-(phosphonomethyl)-glutamine, sphonomethyl)-arginine; N.N-bis(phosphonomethyl)-aspar N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-iso tic acid: N,N-bis(phosphonomethyl)-asparagines; N,N-bis leucine, N-(phosphonomethyl)-leucine, N-(phosphonom (phosphonomethyl)-cysteine; N.N-bis(phosphonomethyl)- ethyl)-lysine, N-(phosphonomethyl)-methionine, glycine; N.N-bis(phosphonomethyl)-glutamic acid; N.N- N-(phosphonomethyl)-phenylalanine, N-(phosphonom bis(phosphonomethyl)-glutamine; N,N- ethyl)-proline, N-(phosphonomethyl)-serine, N-(phospho bis(phosphonomethyl)-histidine; N,N- nomethyl)-threonine, N-(phosphonomethyl)-tryptophan, bis(phosphonomethyl)-isoleucine; N,N- N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)- bis(phosphonomethyl)-leucine; N,N- valine. These are within the category of N-(phosphonom bis(phosphonomethyl)-lysine; N.N-bis(phosphonomethyl)- ethyl)-amino acids. methionine; N,N-bis(phosphonomethyl)-phenylalanine: N,N-bis(phosphonomethyl)-serine; N.N-bis(phosphonom 0050. The preferred mono-substituted related amino ethyl)-threonine; N.N-bis(phosphonomethyl)-tryptophan; acids include: N,N-bis(phosphonomethyl)-tyrosine; N,N-bis(phospho 0051 N-(phosphonomethyl)-3-alanine, N-(phosphonom nomethyl)-valine: N,N'-bis(phosphonomethyl)-arginine: ethyl)-y-aminobutanoic acid, N-(phosphonomethyl)-3-ami N,N'-bis(phosphonomethyl)-histidine; N,N'-bis(phospho noisobutanoic acid, N-(phosphonomethyl)-anserine, nomethyl)-lysine and N,N'-bis(phosphonomethyl)-tryp N-(phosphonomethyl)-aminolevulinic acid, N-(phospho tophan. These compounds are within the category of deriva nomethyl)-camosine, N-(phosphonomethyl)-canaline, tives. N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)- citrulline, N-(phosphonomethyl)-creatine, N-(phosphonom 0054 The preferred di- or bis-substituted related amino ethyl)-creatinine, N-(phosphonomethyl)-cysteine Sulfinic acids and derivatives include: acid, N-(phosphonomethyl)-cystine, N-(phosphonomethyl)- 0055 N.N-bis(phosphonomethyl)-3-alanine; N.N-bis cycloserine, N-(phosphonomethyl)-dopaN-(phosphonom (phosphonomethyl)-y-aminobutanoic acid: N,N-bis(pho ethyl)-3,4-dihydroxyphenylalanine, N-(phosphonomethyl)- sphonomethyl)-3-aminoisobutanoic acid; N,N-bis(phospho dopamine (hydroxytyramine), N-(phosphonomethyl)- nomethyl)-anserine; N,N-bis(phosphonomethyl)- ethionine, N-(phosphonomethyl)-glutathione, aminolevulinic acid; N,N-bis(phosphonomethyl)-carnosine; N-(phosphonomethyl)-guanidinoacetic acid, N-(phospho N,N-bis(phosphonomethyl)-canaline; N,N-bis(phospho nomethyl)-3-guanidinopropanoic acid, N-(phosphonom nomethyl)-canavanine; N.N-bis(phosphonomethyl)-citrul ethyl)-4-guanidinobutanoic acid, -(phosphonomethyl)-ho line; N.N-bis(phosphonomethyl)-creatine; N.N-bis(pho mocamosine, N-(phosphonomethyl)-homocysteine, sphonomethyl)-creatinine; N,N-bis(phosphonomethyl)- N-(phosphonomethyl)-homoserine, N-(phosphonomethyl)- cysteine sulfinic acid: N,N-bis(phosphonomethyl)-cystine: 4-hydroxyphenylglycine, N-(phosphonomethyl)-hydroxy N,N-bis(phosphonomethyl)-cycloserine; N.N-bis(phospho glutamic acid, N-(phosphonomethyl)-hydroxylysine, nomethyl)-dopa (3; N,N-bis(phosphonomethyl)-4-dihy N-(phosphonomethyl)-hydroxyproline, N-(phosphonom droxyphenylalanine); N,N-bis(phosphonomethyl)-dopam ethyl)-hypusine, N-(phosphonomethyl)-homoarginine, ine (hydroxytyramine); N,N-bis(phosphonomethyl)- N-(phosphonomethyl)-homocitrulline, N-(phosphonom ethionine; N.N-bis(phosphonomethyl)-glutathione; N.N- ethyl)-homocystine, N-(phosphonomethyl)-homophenylala bis(phosphonomethyl)-guanidinoacetic acid; N,N- nine, N-(phosphonomethyl)-homotryptophan, N-(phospho bis(phosphonomethyl)-3-guanidinopropanoic acid; N.N- nomethyl)-hydroxylysine, N-(phosphonomethyl)- bis(phosphonomethyl)-4-guanidinobutanoic acid; N.N- hydroxyarginine, N-(phosphonomethyl)- bis(phosphonomethyl)-homocamosine; N,N- hydroxyhomoarginine, N-(phosphonomethyl)- bis(phosphonomethyl)-homocysteine; N,N- US 2007/01 6 1543 A1 Jul. 12, 2007 bis(phosphonomethyl)-homoserine; N.N-bis(phosphonom with stirring while the container was cooled externally with ethyl)-4-hydroxyphenylglycine; a cold-water bath. The mixture was filtered, and the filtrate bis(phosphonomethyl)-hydroxyglutamic acid; was cooled with an ice-water bath. From the filtrate, bis(phosphonomethyl)-hydroxylysine; N-(phosphonomethyl)-amino acid was obtained as a pre bis(phosphonomethyl)-hydroxyproline; cipitate which was washed with cold dilute HCl and cold bis(phosphonomethyl)-hypusine; water. The product thus obtained was identified by routine bis(phosphonomethyl)-homoarginine; chemical methods. bis(phosphonomethyl)-homocitrulline; bis(phosphonomethyl)-homocystine; 0061 The ester form of an N-(phosphonomethyl)-amino bis(phosphonomethyl)-homophenylalanine; acid was synthesized by a conventional process which bis(phosphonomethyl)-homotryptophan; included heating the N-(phosphonomethyl)-amino acid in bis(phosphonomethyl)-hydroxylysine; anhydrous alcohol containing HCl gas. Methyl, ethyl, propyl bis(phosphonomethyl)-hydroxyarginine; and isopropyl esters of an N-(phosphonomethyl)-amino acid bis(phosphonomethyl)-hydroxyhomoarginine; were readily synthesized by the above simple process. For bis(phosphonomethyl)-hydroxycitrulline; example, N-(phosphonomethyl)-L-proline ethyl ester, bis(phosphonomethyl)-hydroxyomithine; N-(phosphonomethyl)-L-tyrosine ethyl ester, N-(phospho bis(phosphonomethyl)-hydroxyvaline; nomethyl)-D-4-hydroxyphenylglycine ethyl ester, bis(phosphonomethyl)-indospicine; N-(phosphonomethyl)-glycine propyl ester and bis(phosphonomethyl)-methoxinine; N-(phosphonomethyl)-glycine isopropyl ester were synthe bis(phosphonomethyl)-methylarginine; sized from their correspondent N-(phosphonomethyl)- bis(phosphonomethyl)-methylhistidine; amino acids by the above process. bis(phosphonomethyl)-methylysine; 0062) The amide form of an N-(phosphonomethyl)- bis(phosphonomethyl)-methylomithine; amino acid was also synthesized by a conventional process bis(phosphonomethyl)-methylserine; which included reaction of an N-(phosphonomethyl)-amino bis(phosphonomethyl)-norvaline; acid methyl ester with ammonia gas in anhydrous methanol. bis(phosphonomethyl)-Omithine; For example, N-(phosphonomethyl)-glycinamide was Syn bis(phosphonomethyl)-oxalysine; thesized from N-(phosphonomethyl)-glycine methyl ester bis(phosphonomethyl)-penicillamine (N-phosphonomethyl by the above process. dimethylcysteine); N,N-bis(phosphonomethyl)- phenylglycine; N.N-bis(phosphonomethyl)-3-phenylserine; 0063. The N-(phosphonoalkyl)-amino acids and related N,N-bis(phosphonomethyl)-sarcosine (N-phosphonom compounds can be synthesized by the same procedure ethyl-N-methyl-glycine); N,N-bis(phosphonomethyl)-sero except that chloromethyl phosphonic acid is replaced by tonin (N-phosphonomethyl-hydroxytryptamine); N,N-bis chloroalkyl phosphonic acid. (phosphonomethyl)-taurine; N.N-bis(phosphonomethyl)- 0064. By using the above process the following specific tryptamine; N.N-bis(phosphonomethyl)-tyramine and N,N'- N-(phosphonomethyl)-amino acids and related compounds bis(phosphonomethyl)-Omithine. These compounds are have been synthesized: within the category of derivatives. 0065 N-(phosphonomethyl)-asparagine, N-(phospho 0056. Any of the above phosphonomethyl-amino acids, nomethyl)-cysteine, N-(phosphonomethyl)-glycine, related compounds and derivatives thereof can be present as N-(phosphonomethyl)-glutamic acid, N-(phosphonom a free acid, salt, or partial salt with organic or inorganic ethyl)-glutamine, N-(phosphonomethyl)-proline, alkali, lactone, amide, ester or in Stereoisomeric or non N-(phosphonomethyl)-serine, N-(phosphonomethyl)-ty Stereoisomeric form. rosine, N-(phosphonomethyl)-y-aminobutanoic acid, 0057. As an illustration, N-(phosphonomethyl)-proline N-(phosphonomethyl)-creatine, N-(phosphonomethyl)- includes for example, N-(phosphonomethyl)-L-proline; creatinine, N-(phosphonomethyl)-glutathione, N-(phospho N-(phosphonomethyl)-L-proline sodium salt; N-(phospho nomethyl)-4-hydroxyphenylglycine, N-(phosphonomethyl)- nomethyl)-L-prolinamide, N-(phosphonomethyl)-L-proline omithine, and N-(phosphonomethyl)-tyramine. methyl ester, N-(phosphonomethyl)-L-proline ethyl ester, 0066. A composition comprising an N-(phosphonoalkyl)- N-(phosphonomethyl)-L-proline propyl ester and amino acid, a related compound or derivative of the present N-(phosphonomethyl)-L-proline isopropyl ester. invention, preferably an N-(phosphonomethyl)-amino acid, a related compound or derivative thereof is believed to be 0.058 Synthesis of N-(Phosphonomethyl)-Amino Acids cosmetically or therapeutically beneficial or effective and and Related Compounds Among different syntheses, the can be administered topically or systemically to a mammal, most convenient and simplest method is the following including a human, Subject in need of prevention or treat process which is modified from the examples described in ment of cosmetic conditions, dermatological disorders, or U.S. Pat. No. 3,799,758, the disclosure of which is hereby diseases associated with the nervous, vascular, musculosk incorporated by reference herein. eletal or cutaneous system, or others. 0059. In general, most N-(phosphonomethyl)-amino 0067 For topical administration, a composition compris acids and related compounds can be synthesized by the ing an N-(phosphonoalkyl)-amino acid, a related compound following exemplary, non-limiting method. or derivative of the present invention, preferably an 0060 An amino acid (1.1 mole) and chloromethyl phos N-(phosphonomethyl)-amino acid a related compound or phonic acid (1 mole) in 300 ml of 8N NaOH were heated at derivative of the present invention, can be topically applied 100° C. for 24 hours. After the reaction mixture was cooled one to three times, and preferably twice, daily to the lesions to room temperature, 250 ml of 12N HCl was slowly added or the cutaneous sites associated with cosmetic conditions or US 2007/01 6 1543 A1 Jul. 12, 2007 medical disorders or diseases. The topical application can nomethyl)-argininamide, N-(phosphonomethyl)-arginine continue until the symptom, cosmetic condition, medical ethyl ester, N-(phosphonomethyl)-lysine, N-(phosphonom disorder or disease has been eradicated or substantially ethyl)-lysinamide, N-(phosphonomethyl)-lysine ethyl ester, improved. The treatment period depends on the condition or N-(phosphonomethyl)-creatine and N-(phosphonomethyl)- severity of the disorder or disease, and also depends on the creatinine. individual Subject. Examples of conditions, disorders and 0072. In accordance with preferred embodiments of the diseases associated with nervous, vascular, musculoskeletal invention, a composition is provided comprising at least one or cutaneous system, or others include, without limitation compound selected from the group consisting of an pains, pruritus, inflammation, erythema, dermatitis, acne, N-(phosphonoalkyl)-amino acid, a related compound or rosacea, eczema, severe dry skin, ichthyosis, age spots, derivative of the present invention, preferably an psoriasis, wrinkles, photoaging skin, pigmented skin, and N-(phosphonomethyl)-amino acid or derivative thereof, as dark skin to be lightened. free acid, ester, amide, lactone or salt form (which includes 0068. As used herein, “percent” or “6” concerning an partial salts) present in a therapeutically or cosmetically amount of an ingredient or component means weight percent effective amount and in a pharmaceutically or cosmetically of the ingredient or component with respect to the overall acceptable vehicle for topical or systemic treatment of composition, unless otherwise indicated. disorders associated with nervous, vascular, musculoskeletal or cutaneous system. In one embodiment of the invention, 0069. For example, human subjects having severe dry the composition further comprises a cosmetic, pharmaceu skin or ichthyosis, topically applied 1%-5% N-(phospho tical or other topically active agent for synergetic or syner nomethyl)-glycine creams to lesions for 2 to 3 weeks. After gistic effects. 2 to 3 weeks of topical application, the thick and scaly skin disappeared and the skin became Smooth and normal in 0073. These cosmetic, pharmaceutical or other topically appearance. Clinical evaluation was judged to be 90% to active agent includes any one or more of an agent selected 100% improvement compared to the untreated condition or from hydroxyacids, ketoacids and related compounds; phe when using a vehicle control. nyl alpha acyloxyalkanoic acids and derivatives; N-acyl aldosamines, N-acylamino acids and related N-acyl com 0070 For systemic administration, a composition com pounds; local analgesics and anesthetics; anti-acne agents; prising an N-(phosphonoalkyl)-amino acid, a related com anti-bacterial agents; anti-yeast agents; anti-fungal agents; pound or derivative of the present invention, preferably an anti-viral agents; anti-infective agents; anti-dandruff agents: N-(phosphonomethyl)-amino acid of the present invention, anti-dermatitis agents; anti-eczema agents; anti-histamine can be administered by injection, infusion or oral intake, or agents; anti-pruritic agents; anti-emetics; anti-motion sick otherwise, with the preferred route being oral administra ness agents; anti-inflammatory agents; anti-hyperkeratotic tion. A composition comprising an N-(phosphonoalkyl)- agents; antiperspirants; anti-psoriatic agents; anti-rosacea amino acid, a related compound or derivative of the present agents; anti-seborrheic agents; hair conditioners and hair invention, preferably an N-(phosphonomethyl)-amino acid, treatment agents; anti-aging and anti-wrinkle agents; anti a related compound or derivative can be taken orally one to anxiety agents; anti-convulsant agents; anti-depressant three times, and preferably twice, daily for prevention or agents; Sunblock and Sunscreen agents; skin lightening treatment of disorders and diseases associated with nervous, agents; depigmenting agents; astringents; cleansing agents: vascular, musculoskeletal or cutaneous system, or others. corn, callus or wart removing agents; skin plumping agents; The oral administration can continue until the symptom, skin Volumizing agents; skin firming agents; matrix metal cosmetic condition, medical disorder or disease has been loproteinase (MMP) inhibitors; topical cardiovascular eradicated or Substantially improved. The symptoms or agents; wound-healing agents; gum disease or oral care disorders include, without limitation, pains, pruritus, inflam agents; amino acids; peptides; dipeptides; tripeptides; glu mation, erythema, dermatitis, acne, eczema, dementia, tathione and its derivatives; oligopeptides; polypeptides; Alzheimer's disease, joint pain or Swelling, and arthritis. carbohydrates; aminocarbohydrates; Vitamins; corticoster Oral dosages can be about 50 mg to about 500 mg daily, oids; tanning agents; hormones and retinoids. preferably divided into equal dosages of about 25 mg to 0074 Non-limiting specific examples of particular cos about 250 mg taken twice daily. metic, pharmaceutical or other topically active agents, as 0071. The particularly preferred N-(phosphonomethyl)- stated or as free base, free acid, ester, amide, lactone or salt amino acids useful in the embodiments described herein, form, include for synergetic or synergistic effects: abacavir, and that can be administered topically or systemically abciximab, acamprosate, acarbose, acebutolol, acetami include N-(phosphonomethyl)-asparagine, N-(phosphonom nophen, acetaminosalol, acetazolamide, acetic acid, aceto ethyl)-asparaginamide, N-(phosphonomethyl)-glycine, hydroxamic acid, N-acetylcysteine and its esters, N-acetyl N-(phosphonomethyl)-glycinamide, N-(phosphonomethyl)- glutathione and its esters, acitretin, aclometaSone glycine ethyl ester, N-(phosphonomethyl)-glycine propyl dipropionate, acrivastine, acthrel, actidose, actigall, acyclo ester, N-(phosphonomethyl)-glycine isopropyl ester, Vir, adalimumab, adapalene, adefovir dipivoxil, adenosine, N-(phosphonomethyl)-proline, N-(phosphonomethyl)-proli agallsidase, albendazole, albumin, albuterol, aldesleukin, namide, N-(phosphonomethyl)-proline ethyl ester, alefacept, alemtuzumab, alendronate, alfuzosin, alitretinoin, N-(phosphonomethyl)-proline propyl ester, N-(phospho allantoin, allium, allopurinol, alloxanthine, almotriptan, nomethyl)-proline isopropyl ester, N-(phosphonomethyl)- alosetron, alpha tocopheral, alpha-proteinase, alprazolam, glutamic acid, N-(phosphonomethyl)-glutamic acid diethyl alprenolol, alprostadil, alteplase, altretamine, aluminum ester, N-(phosphonomethyl)-glutamine, N-(phosphonom acetate, aluminum chloride, aluminum chlorohydroxide, ethyl)-glutaminamide, N-(phosphonomethyl)-glutamine aluminum hydroxide, amantadine, amifostine, amiloride, ethyl ester, N-(phosphonomethyl)-arginine, N-(phospho aminacrine, amino acid, aminobenzoate, p-aminobenzoic US 2007/01 6 1543 A1 Jul. 12, 2007 acid, aminocaproic acid, aminohippurate, aminolevulinic pine, homosalate, hydralazine, hydrochlorothiazide, hydro acid, aminosalicylic acid, amiodarone, amitriptyline, amlo cortisone, hydrocortisone 21-acetate, hydrocortisone dipine, amocarzine, amodiaquin, amorolfine, amoxapine, 17-butyrate, hydrocortisone 17-valerate, hydrogen peroxide, amoxicillin, amphetamine, amphotericin, amplicillin, hydromorphone, hydroquinone, hydroquinone monoether, amprenavir, anagrelide, anakinra, anastroZole, anisindione, hydroxy Zine, hyoscyamine, hypoxanthine, ibuprofen, ich anthralin, antihemophilic, antithrombin, anti-thymocyte, thammol. idarubicin, imatinib, imipramine, imiquimod, antivenin, apomorphine, aprepitant, aprotinin, arbutin, arga indinavir, indomethacin, infliximab, irbesartan, irinotecan, troban, aripiprazole, arnica, ascorbic acid and its esters, isoetharine, isoproterenol, itraconazole, kanamycin, ket ascorbyl palmitate, aspirin, atazanavir, atenolol, atomoxet amine, ketanserin, ketoconazole, ketoprofen, ketotifen, kojic ine, atorvastatin, atovaquone, atropine, azathioprine, azelaic acid, labetalol, lactic acid, lactobionic acid, lamivudine, acid, azelastine, azithromycin, baclofen, bacitracin, bal lamotrigine, lanSoprazole, letrozole, leuprolide, leval Salazide, balsam, basiliximab, beclomethasone dipropi buterol, levofloxacin, lidocaine, linezolid, lobeline, lorata onate, bemegride, benazepril, bendroflumethiazide, ben dine, loperamide, losartan, loxapine, lysergic diethylamide, Zocaine, benzonatate, benzophenone, benzoyl peroxide, mafenide, malic acid, maltobionic acid, mandelic acid, benztropine, bepridil, beta carotene, betamethasone dipro maprotiline, mebendazole, mecamylamine, meclizine, pionate, betamethasone Valerate, betaxolol, bethanechol, meclocycline, memantine, menthol, meperidine, mepiv bevacizumab, bexarotene, bicalutamide, bimatoprost, acaine, meduinol, mercaptopurine, mescaline, metaneph bioflavonoids, biotin, biperiden, bisacodyl, bisoprolol, biva rine, metaproterenol, metaraminol, metformin, methadone, lirudin, bortezomib, bosentan, botulinum, brimonidine, brin methamphetamine, methotrexate, methoxamine, methyl Zolamide, bromocriptine, brompheniramine, budesonide, dopa esters, methyldopamide, 3.4-methylenedioxymetham bumetanide, bupivacaine, buprenorphine, bupropion, buri phetamine, methylactic acid, methyl nicotinate, meth mamide, buspirone, busulfan, butabarbital, butalbital, buten ylphenidate, methyl salicylate, metiamide, metolaZone, afine, butoconazole, butorphanol, butylaminobenzoate, cab metoprolol, metronidazole, mexiletine, miconazole, mida ergoline, caffeic acid, caffeine, calcipotriene, calcitonin Zolam, midodrine, miglustat, minocycline, minoxidil, mir salmon, calcitriol, calfactant, camellia sinensis, camphor, tazapine, mitoxantrone, moexiprilat, molindone, monoben candesartan cilexetil, capecitabine, capreomycin, capsaicin, Zone, morphine, moxifloxacin, moxonidine, mupirocin, captopril, carbamazepine, carbamide peroxide, carbidopa, nadolol, naftifine, nalbuphine, nalmefene, naloxone, carbinoxamine, cefditoren pivoxil, cefepime, cefpodoxime naproxen, nefazodone, nelfinavir, neomycin, nevirapine, proxetil, celecoxib, cetirizine, cevimeline, chitosan, chlor nicardipine, nicotine, nifedipine, nimodipine, nisoldipine, diazepoxide, chlorhexidine, chloroquine, chlorothiazide, nitrofurantoin, nizatidine, norepinephrine, nystatin, octo chloroxylenol, chlorpheniramine, chlorpromazine, chlorpro pamine, octreotide, octyl methoxycinnamate, octyl salicy pamide, ciclopiroX, ciloStaZol, cimetidine, cinacalcet, cipro late, ofloxacin, olanzapine, olmesartan medoxomil, olopata floxacin, citalopram, citric acid, cladribine, clarithromycin, dine, omeprazole, ondansetron, oxiconazole, oxotremorine, clemastine, clindamycin, clioquinol, clobetasol propionate, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padi clocortolone pivalate, clomiphene, clonidine, clopidogrel, mate O, palonosetron, pantothenic acid, pantoyl lactone, clotrimazole, clozapine, coal tar, coal tar extracts (LCD), paroxetine, pemoline, penciclovir, penicillamine, penicil codeine, cromolyn, crotamiton, cyclizine, cyclobenzaprine, lins, pentazocine, pentobarbital, pentostatin, pentoxifylline, cycloserine, cytarabine, dacarbazine, dalfopristin, dapsone, pergolide, perindopril, permethrin, phencyclidine, daptomycin, daunorubicin, deferoxamine, dehydroepi phenelZine, pheniramine, phenmetrazine, phenobarbital, androsterone, delavirdine, desipramine, desloratadine, des phenol, phenoxybenzamine, phentolamine, phenylephrine, mopressin, desoximetasone, dexamethasone, dexmedetomi phenylpropanolamine, phenytoin, physostigmine, pilo dine, dexmethylphenidate, dexraZoxane, carpine, pimecrolimus, pimozide, pindolol, pioglitaZone, dextroamphetamine, diazepam, diclofenac, dicyclomine, pipamazine, piperonyl butoxide, pirenzepine, podofilox, didanosine, dihydrocodeine, dihydromorphine, diltiazem, poVidone iodine, pramipexole, pramoxine, praZosin, pred 6,8-dimercaptooctanoic acid (dihydrolipoic acid), diphen nisone, prenalterol, prilocaine, procainamide, procaine, pro hydramine, diphenoxylate, dipyridamole, disopyramide, carbazine, promazine, promethazine, promethazine propi dobutamine, dolfetilide, dolasetron, donepezil, dopa esters, Onate, propafenone, propoxyphene, propranolol. dopamide, dopamine, dorzolamide, doxepin, doxorubicin, propylthiouracil, protriptyline, pseudoephedrine, pyrethrin, doxycycline, doxylamine, doxepin, dulloxetine, dyclonine, pyrilamine, pyrimethamine, quetiapine, quinapril, quineth econazole, efalizumab, eflomithine, eletriptan, emitricitab aZone, quinidine, quinupristin, rabeprazole, reserpine, resor ine, enalapril, ephedrine, epinephrine, epinine, epirubicin, cinol, retinal, 13-cis retinoic acid, retinoic acid, retinol, eptifibatide, ergotamine, erythromycin, escitalopram, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid, esmolol, esomeprazole, estazolam, estradiol, etanercept, ribonolactone, rifampin, rifapentine, rifaximin, riluzole, ethacrynic acid, ethinyl estradiol, etidocaine, etomidate, rimantadine, risedronic acid, risperidone, ritodrine, rivastig famciclovir, famotidine, felodipine, fentanyl, ferulic acid, mine, rizatriptan, ropinirole, ropivacaine, Salicylamide, Sali fexofenadine, flecainide, fluconazole, flucytosine, fluocino cylic acid, Salmeterol, Scopolamine, Selegiline, selenium lone acetonide, fluocinonide, 5-fluorouracil, fluoxetine, Sulfide, serotonin, Sertaconazole, sertindole, Sertraline, shale fluiphenazine, flurazepam, fluticaSone propionate, fluvoxam tar, Sibutramine, Sildenafil. Sotalol, Streptomycin, Strychnine, ine, formoterol, furosemide, galactarolactone, galactonic Sulconazole, Sulfacetamide, Sulfabenz, Sulfabenzamide, Sul acid, galactonolactone, galantamine, gatifloxacin, gefitinib, fabromomethazine, Sulfacetamide (sodium Sulfacetamide), gemcitabine, gemifloxacin, glucarolactone, gluconic acid, Sulfachlorpyridazine, Sulfacytine, Sulfadiazine, Sul gluconolactone, glucuronic acid, glucuronolactone, glycolic fadimethoxine, Sulfadoxine, Sulfaguanole, Sulfalene, Sul acid, griseofulvin, guaifenesin, guanethidine, N-guanylhis famethizole, Sulfamethoxazole, Sulfanilamide, Sulfapyra tamine, haloperidol, haloprogin, hexylresorcinol, homatro Zine, Sulfapyridine, Sulfasalazine, Sulfasomizole, US 2007/01 6 1543 A1 Jul. 12, 2007

Sulfathiazole, Sulfisoxazole, Sulfur, tacrolimus, tadalafil. or ammoniated glycyrrhizinate to a solution comprising the tamsulosin, tartaric acid, tazarotene, tegaserod, tellithromy N-(phosphonoalkyl)-amino acid. The preferred concentra cin, telmisartan, temozolomide, tenofovir disoproxil, tera tion of the gelling agent may be about 0.1% to about 4%. In Zosin, terbinafine, terbutaline, terconazole, terfenadine, tet the preparation of shampoo, the N-(phosphonoalkyl)-amino racaine, tetracycline, tetrahydrozoline, thalidomide, acid, related compound or derivative thereof is first dis theobromine, theophylline, thiabendazole, thioctic acid Solved in water or propylene glycol, and the Solution thus (lipoic acid), thioridazine, thiothixene, thymol, tiagabine, obtained is mixed with a shampoo base. Concentrations of timolol, tinidazole, tioconazole, tirofiban, tizanidine, tobra the N-(phosphonoalkyl)-amino acid, related compound or mycin, tocainide, tolazoline, tolbutamide, tolnaftate, toltero derivative thereofused in gel or shampoo form are the same dine, tramadol, tranylcypromine, traZodone, triamcinolone as described above regarding solutions. acetonide, triamcinolone diacetate, triamcinolone hexac 0080. To prepare a combination composition for syner etonide, triamterene, triazolam, triclosan, triflupromazine, getic or synergistic effects, a cosmetic, pharmaceutical or trimethoprim, trimipramine, tripelennamine, triprolidine, other agent is incorporated into any one of the above tromethamine, tropic acid, tyramine, undecylenic acid, urea, compositions by dissolving or mixing the agent into the urocanic acid, ursodiol, Valacyclovir, Vardenafil. Venlafax formulation. Other forms of compositions of the present ine, Verapamil, Vitamin E acetate, Voriconazole, warfarin, invention for delivery of the N-(phosphonoalkyl)-amino wood tar, Xanthine, Zafirlukast, Zaleplon, Zinc pyrithione, acid, a related compound or derivative of the present inven Ziprasidone, Zolmitriptan and Zolpidem. tion, preferably an N-(phosphonomethyl)-amino acid, are 0075 General Preparations readily blended, prepared or formulated by those skilled in the art in view of the present disclosure. For systemic 0.076 Compositions of the present invention comprising administration the N-(phosphonoalkyl)-amino acid, a an N-(phosphonoalkyl)-amino acid, preferably an related compound or derivative of the present invention, N-(phosphonomethyl)-amino acid, a related compound or preferably an N-(phosphonomethyl)-amino acid, can be derivative of the present invention can be formulated as an formulated for oral administration or for parenteral injection injectable or infusible solution or other formulation or as a or infusion. In oral preparations, the N-(phosphonoalkyl)- topical Solution, gel, lotion, cream, ointment, shampoo, amino acid can be formulated in tablet form or in gelatin spray, Stick, pad, powder, masque, mouth rinse or wash, capsules with or without mixing with gelatin powder. Each vaginal gel or preparation, or other form acceptable for use tablet or capsule can contain about 10 mg to about 300 mg on skin, nail, hair, oral mucosa, vaginal or anal mucosa, of the N-(phosphonomethyl)-amino acid as free acid, salt, mouth or gums. amide, ester or lactone form. For parenteral injection or 0.077 To prepare a solution composition of the present infusion, the N-(phosphonomethyl)-amino acid is prepared invention, at least one N-(phosphonoalkyl)-amino acid, under Sterilized conditions, usually in a concentration of preferably an N-(phosphonomethyl)-amino acid, a related about 1% to about 10% in water, propylene glycol and/or compound or derivative is dissolved in a solution prepared non-aqueous vehicle. from water, ethanol, propylene glycol, butylene glycol, and/or other pharmaceutically or cosmetically acceptable 0081. The present invention will now be described in vehicle. The concentration of a single N-(phosphonoalkyl)- more detail with reference to the following non-limiting amino acid, preferably an N-(phosphonomethyl)-amino examples. In the initial tests for comparative studies, a acid, a related compound or derivative, or the total concen control vehicle was always included. It was discovered that tration of all N-(phosphonomethyl)-amino acids where the all the vehicle controls gave the same results as that of the composition comprises more than one N-(phosphonom untreated skin sites; no detectable effects of the controls ethyl)-amino acid, can be about 0.01% to about 99.9%, with have been found as judged by clinical evaluation. a preferred concentration of about 0.1% to about 50%, and 0082 For subjective disorders such as pain, itch or the a more preferred concentration of about 0.5% to about 10%. like, the therapeutic effects were evaluated or judged by the Subjects or patients; for example, if the pain or itch had 0078. To prepare a topical composition in lotion, cream disappeared within hours or days. For other detectable or ointment form, the N-(phosphonoalkyl)-amino acid, a symptoms or syndromes, the therapeutic effects or improve related compound or derivative of the present invention, preferably an N-(phosphonomethyl)-amino acid, is first dis ments were evaluated or judged by medical professionals. Solved in water, ethanol, propylene glycol, and/or other EXAMPLE 1. vehicle, and the solution thus obtained is mixed with a desired base or pharmaceutically or cosmetically acceptable 0083. In one of the studies related to skin changes asso vehicle to make a lotion, cream or ointment. Typical oint ciated with aging, skin thickness was measured by microme ments can be made readily with an oil-in-water emulsion, ter calipers as follows: such as hydrophilic ointment U.S.P., as is well known to 0084. The skin was grasped with a 2x6 cm metal hinge, those skilled in the art in view of the present disclosure. the internal faces of which were coated with emery cloth to Concentrations of the N-(phosphonoalkyl)-amino acid are prevent slippage, and manually squeezed to threshold Sub the same as described above regarding Solutions. ject discomfort. Combined thickness of two whole-skin 0079 A topical composition of the instant invention can layers including thickness of the two hinge leaves was also be formulated in a gel or shampoo form. A typical gel measured with micrometer calipers. Thickness of the two composition is formulated by the addition of a gelling agent hinge leaves was subtracted to determine the actual thick Such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl ness of the two whole-skin layers. Triplicate measurements alcohol, polyduatemiums, hydroxyethylcellulose, hydrox on treated sites were done and an average number was used ypropylcellulose, hydroxypropylmethylcellulose, carbomer for calculation of the skin thickness. US 2007/01 6 1543 A1 Jul. 12, 2007

EXAMPLE 2 0090. A male subject, age 86, had chronic plaque pso riasis with erythema, moderately thick and silvery scales. 0085 N-(phosphonomethyl)-glycine (5 g) was sus The subject topically applied twice daily the above white pended in water (30 ml) and propylene glycol (10 ml), and cream containing 5% N-(phosphonomethyl)-glycine ethyl concentrated ammonium hydroxide (2 ml) was added with ester to one psoriatic lesion for two weeks. At the end of two stirring. The Suspension became a clear Solution, and was weeks, the erythema and silvery scales improved substan mixed with hydrophilic ointment (oil-in-water emulsion, 53 tially, and the treated skin had 50% improvement in contrast g). The white cream thus formulated had pH 3.8 and to the untreated or vehicle control as judged by clinical contained 5% N-(phosphonomethyl)-glycine. A male sub evaluation. ject, age 35, who had X-linked ichthyosis with severe dry skin, having thick and rough skin with adherent scales, EXAMPLE 5 topically applied the above 5% N-(phosphonomethyl)-gly cine cream to an involved skin site twice daily for two 0091 N-(phosphonomethyl)-L-tyrosine (5 g) was dis weeks. After one week of topical application, the adherent Solved in warm propylene glycol (40 ml), and the solution scales disappeared, and the skin became Smooth and had thus obtained was mixed with hydrophilic ointment (oil-in 50% improvement in contrast to the untreated or vehicle water emulsion, 55 g). The white cream thus formulated had control as judged by clinical evaluation. After two weeks of pH 2.3 and contained 5% N-(phosphonomethyl)-L-tyrosine. topical application, the treated skin became normal in 0092. A male subject, age 35, who had X-linked ichthyo appearance, and had 100% improvement in contrast to the sis with severe dry skin, having thick and rough skin with untreated or vehicle control as judged by clinical evaluation. adherent scales, topically applied the above 5% N-(phospho The above results show that a representative N-(phospho nomethyl)-L-tyrosine cream to an involved skin site twice nomethyl)-amino acid would be therapeutically effective for daily for 12 days. After 12 days of topical application, most topical treatment of disturbed keratinization and hyperkera adherent Scales disappeared and the skin became Smooth, totic conditions including dry skin, severe dry skin, ichthyo and had 75% improvement in contrast to the untreated or sis, calluses, keratoses, acne, rosacea, blemished skin, pso vehicle control as judged by clinical evaluation. riasis and age spots. 0093. The above results show that another representative EXAMPLE 3 N-(phosphonomethyl)-amino acid would be therapeutically effective for topical treatment of disturbed keratinization and 0.086 N-(phosphonomethyl)imino-diacetic acid (5 g) hyperkeratotic conditions including dry skin, severe dry was Suspended in water (15 ml) and propylene glycol (10 skin, ichthyosis, calluses, keratoses, acne, rosacea, blem ml), and concentrated ammonium hydroxide (3 ml) was ished skin, psoriasis and age spots. added with stirring. The Suspension became a clear Solution, and was mixed with hydrophilic ointment (oil-in-water EXAMPLE 6 emulsion 67 g). The white cream thus formulated had pH 3.5 0094 N-(phosphonomethyl)-L-proline (5 g) was sus and contained 5% N-(phosphonomethyl)imino-diacetic pended in water (20 ml), and concentrated ammonium acid. hydroxide (0.8 ml) was added. The solution thus obtained 0087. A male subject, age 35, who had X-linked ichthyo was mixed with hydrophilic ointment (oil-in-water emul sis with severe dry skin, having thick and rough skin with sion, 74.2 g). The white cream thus formulated had pH 3.2 adherent scales, topically applied the above 5% N-(phospho and contained 5% N-(phosphonomethyl)-L-proline. Under nomethyl)imino-diacetic acid cream to an involved skin site the same procedure, a white cream containing 10% twice daily for two weeks. After one week of topical N-(phosphonomethyl)-L-proline was formulated from application, most adherent scales disappeared and the skin N-(phosphonomethyl)-L-proline (10 g), water (20 ml), con had 50% improvement in contrast to the untreated or vehicle centrated ammonium hydroxide (1 ml), and hydrophilic control as judged by clinical evaluation. After two weeks of ointment (oil-in-water emulsion, 69 g). topical application, the scales disappeared completely and 0095. A male subject, age 86, had chronic plaque pso the treated skin became smooth, and had 90% improvement riasis with erythema, moderately thick and silvery scales. in contrast to the untreated or vehicle control as judged by The subject topically applied twice daily the above white clinical evaluation. cream containing 10% N-(phosphonomethyl)-L-proline to 0088. The above results show that another representative one psoriatic lesion for two weeks. At the end of two weeks, N-(phosphonomethyl)-amino acid would be therapeutically the erythema and silvery scales improved very Substantially, effective for topical treatment of disturbed keratinization and and the treated skin had 75% improvement in contrast to the hyperkeratotic conditions including dry skin, severe dry untreated or vehicle control as judged by clinical evaluation. skin, ichthyosis, calluses, keratoses, acne, rosacea, blem 0096. The above results show that yet another represen ished skin, psoriasis and age spots. tative N-(phosphonomethyl)-amino acid would be therapeu tically effective for topical treatment of disturbed keratini EXAMPLE 4 Zation and inflammatory conditions including erythema, 0089 N-(phosphonomethyl)-glycine ethyl ester (5 g) was eczema, dermatitis, dermatoses, itch, psoriasis, acne and dissolved in warm water (20 ml) and propylene glycol (20 OSaCCa. ml), and the solution thus obtained was mixed with hydro EXAMPLE 7 philic ointment (oil-in-water emulsion, 55 g). The white cream thus formulated had pH 1.2 and contained 5% 0097 N-(phosphonomethyl)-DL-asparagine (6 g) was N-(phosphonomethyl)-glycine ethyl ester. dissolved in warm water (30 ml) and propylene glycol (10 US 2007/01 6 1543 A1 Jul. 12, 2007

ml), and the solution thus obtained was mixed with hydro ml), 2-amino-2-methyl-1-propanol (2.5 ml) and hydrophilic philic ointment (oil-in-water emulsion, 54 g). The white ointment (oil-in-water emulsion, 62.5 g). cream thus formulated had pH 2.2 and contained 6% 0104. A male subject, age 86, had chronic plaque pso N-(phosphonomethyl)-DL-asparagine. riasis with erythema, moderately thick and silvery scales. 0.098 N-(phosphonomethyl)-DL-asparagine (5 g) was The subject topically applied twice daily the above white dissolved in warm water (30 ml) and propylene glycol (10 cream containing 5% N-(phosphonomethyl)-glycine propyl ml), and the solution thus obtained was mixed with hydro ester to one psoriatic lesion for two weeks. At the end of two philic ointment (oil-in-water emulsion, 55 g). The white weeks, the erythema and silvery scales improved very cream thus formulated had pH 2.2 and contained 5% substantially, and the treated skin had 75% improvement in N-(phosphonomethyl)-DL-asparagine. contrast to the untreated or vehicle control as judged by 0099. A male subject, age 36, who had X-linked ichthyo clinical evaluation. sis having thick and rough skin with adherent scales, topi 0105 The above results show that still another represen cally applied the 5% N-(phosphonomethyl)-DL-asparagine tative N-(phosphonomethyl)-amino acid derivative would cream to an involved skin site twice daily for three weeks. be therapeutically effective for topical treatment of disturbed After one week of topical application, most adherent scales keratinization and inflammatory conditions including disappeared and the treated site appeared Smooth. The skin erythema, eczema, dermatitis, dermatoses, itch, psoriasis, had 75% improvement in contrast to the untreated or vehicle acne and rosacea. control as judged by clinical evaluation. After three weeks of topical application, the scales disappeared completely and EXAMPLE 10 the treated site felt Smooth and normal in appearance. The 0106 N-(phosphonomethyl)-glycine isopropyl ester (10 skin had 100% improvement in contrast to the untreated or g) was dissolved in water (10 ml), propylene glycol (20 ml) vehicle control as judged by clinical evaluation. and meglumine (N-methyl-D-glucamine, 4 g). The Solution 0100. The above results show that another N-(phospho thus obtained was mixed with hydrophilic ointment (oil-in water emulsion, 56 g). The white cream thus formulated had nomethyl)-amino acid would be therapeutically effective for pH 1.1, and contained 10% N-(phosphonomethyl)-glycine topical treatment of disturbed keratinization and hyperkera isopropyl ester. Under the same procedure, a white cream totic conditions including dry skin, severe dry skin, ichthyo containing 5% N-(phosphonomethyl)-glycine isopropyl sis, calluses, keratoses, acne, rosacea, blemished skin, pso ester was formulated from N-(phosphonomethyl)-glycine riasis and age spots. isopropyl ester (5 g), water (10 ml), propylene glycol (20 EXAMPLE 8 ml), meglumine (2 g) and hydrophilic ointment (63 g). 0.107 A male subject, age 86, had chronic plaque pso 0101. A male subject, age 36, who had hyperpigmented riasis with erythema, moderately thick and silvery scales. dark skin, topically applied 5% N-(phosphonomethyl)-DL The subject topically applied twice daily the above white asparagine cream prepared according to Example 7 to an cream containing 5% N-(phosphonomethyl)-glycine isopro involved skin site twice daily for four weeks. After two pyl ester to one psoriatic lesion for a week. At the end of one weeks of topical application, the treated site had mild week, the erythema and silvery scales improved substan depigmentation and showed lighter skin color as compared tially, and the treated skin had 50% improvement in contrast to untreated skin site. The treated site was 25% lighter in to the untreated or vehicle control as judged by clinical skin color in contrast to the untreated or vehicle control as evaluation. judged by clinical evaluation. After four weeks of topical application, the treated site had substantial reduction in skin EXAMPLE 11 pigmentation. The treated site was 50% lighter in contrast to 0.108 N-(phosphonomethyl)-glycinamide (5 g) was dis the untreated or vehicle control in skin color as judged by solved in water (10 ml) and propylene glycol (30 ml), and clinical evaluation. the mixture thus obtained was mixed with hydrophilic 0102) The above results show that a representative ointment (oil-in-water emulsion, 55 g). The white cream N-(phosphonomethyl)-amino acid would be effective for thus formulated had pH 2.1 and contained 5% N-(phospho topical treatment of hyperpigmented skin, age spots, nomethyl)-glycinamide. Under the same procedure, a white melasma, lentigines, mottled skin, aging related skin cream containing 8% N-(phosphonomethyl)-glycinamide changes, and would be topically effective for skin lighten was formulated from N-(phosphonomethyl)-glycinamide (8 1ng. g), water (10 ml), propylene glycol (30 ml) and hydrophilic ointment (52 g). EXAMPLE 9 0109) A male subject, age 86, had chronic plaque pso 0103 N-(phosphonomethyl)-glycine propyl ester (10 g) riasis with erythema, moderately thick and silvery scales. was dissolved in warm water (20 ml), propylene glycol (10 The subject topically applied twice daily the above white ml) and 2-amino-2-methyl-1-propanol (5 ml). The clear cream containing 8% N-(phosphonomethyl)-glycinamide to solution thus obtained was mixed with hydrophilic ointment one psoriatic lesion for three weeks. At the end of three (oil-in-water emulsion, 55 g). The white cream thus formu weeks, the erythema and silvery scales disappeared almost lated had pH 5.1, and contained 10% N-(phosphonomethyl)- completely, and the treated skin had 90% improvement in glycine propyl ester. Under the same procedure, a white contrast to the untreated or vehicle control as judged by cream containing 5% N-(phosphonomethyl)-glycine propyl clinical evaluation. ester was formulated from N-(phosphonomethyl)-glycine 0110. The above results show that another representative propyl ester (5 g), warm water (20 ml), propylene glycol (10 N-(phosphonomethyl)-amino acid derivative would be US 2007/01 6 1543 A1 Jul. 12, 2007

therapeutically effective for topical treatment of disturbed EXAMPLE 1.4 keratinization and inflammatory conditions including erythema, eczema, dermatitis, dermatoses, itch, psoriasis, 0118 N-(phosphonomethyl)-L-serine (6 g) was dissolved acne and rosacea. in warm propylene glycol (10 ml) and water (30 ml). The solution thus obtained was mixed with hydrophilic ointment EXAMPLE 12 (oil-in-water emulsion, 54 g). The white cream thus formu 0111 N-(phosphonomethyl)-L-tyrosine ethyl ester (5 g) lated had pH 1.7 and contained 6% N-(phosphonomethyl)- was dissolved in warm propylene glycol (20 ml) and water L-serine. (10 ml). The solution thus obtained was mixed with hydro philic ointment (oil-in-water emulsion, 65 g). The white EXAMPLE 1.5 cream thus formulated had pH 1.2 and contained 5% 0119) N-(phosphonomethyl)-L-proline ethyl ester (8 g) N-(phosphonomethyl)-L-tyrosine ethyl ester. was dissolved in water (10 ml), propylene glycol (20 ml) and 0112 A male subject, age 36, who had X-linked ichthyo ethylenediamine (4 ml). The solution thus obtained was sis having thick and rough skin with adherent scales, topi mixed with hydrophilic ointment (oil-in-water emulsion, 58 cally applied the above 5% N-(phosphonomethyl)-L-ty g). The white cream thus formulated had pH 5.9, and rosine ethyl ester cream to an involved skin site twice daily contained 8% N-(phosphonomethyl)-L-proline ethyl ester. for one week. After one week of topical application, most 0.120. A male subject, age 74, having itchy eczema on his adherent scales disappeared and the treated skin had 25% right thigh, topically applied the above 8% N-(phosphonom improvement in contrast to the untreated or vehicle control ethyl)-L-proline ethyl ester cream. The itch disappeared as judged by clinical evaluation. within a few minutes after the topical application. The 0113. The above results show that another N-(phospho treated skin did not itch for the next 8 hours. Therapeutic nomethyl)-amino acid would be therapeutically effective for evaluation was judged to be 100% effective in contrast to the topical treatment of disturbed keratinization and hyperkera untreated or vehicle control for immediate relief of itch. totic conditions including dry skin, severe dry skin, ichthyo 0121 The above result shows that a representative sis, calluses, keratoses, acne, rosacea, blemished skin, pso N-(phosphonomethyl)-amino acid derivative would be riasis and age spots. therapeutically effective for topical treatment of disturbed 0114. A male subject, age 86, had chronic plaque psoria keratinization and inflammatory conditions including sis with erythema, moderately thick and silvery scales. The erythema, eczema, dermatitis, dermatoses, itch, psoriasis, subject topically applied twice daily the above white cream acne and rosacea. containing 5% N-(phosphonomethyl)-L-tyrosine ethyl ester to one psoriatic lesion for two weeks. At the end of two EXAMPLE 16 weeks, the erythema and silvery scales improved noticeably and the treated skin had 25% improvement in contrast to the 0.122 N-(phosphonomethyl)-L-serine ethyl ester (6 g) untreated or vehicle control as judged by clinical evaluation. was dissolved in warm propylene glycol (30 ml). The solution thus obtained was mixed with hydrophilic ointment 0115 The above results show that another representative (oil-in-water emulsion, 64 g). The white cream thus formu N-(phosphonomethyl)-amino acid derivative would be lated had pH 1.3 and contained 6% N-(phosphonomethyl)- therapeutically effective for topical treatment of disturbed L-serine ethyl ester. keratinization and inflammatory conditions including erythema, eczema, dermatitis, dermatoses, itch, psoriasis, EXAMPLE 17 acne and rosacea. 0123 N-(phosphonomethyl)-creatine (7 g) was dissolved EXAMPLE 13 in water (30 ml) and propylene glycol (10 ml), and the 0116 N-(phosphonomethyl)-D-4-hydroxyphenylglycine solution thus obtained was mixed with hydrophilic ointment (5 g) was dissolved in water (10 ml) and propylene glycol (oil-in-water emulsion, 53 g). The white cream thus formu (20 ml), and the mixture thus obtained was mixed with lated had pH 1.8 and contained 7% N-(phosphonomethyl)- hydrophilic ointment (oil-in-water emulsion, 65 g). The creatine. Under the same procedure, a white cream contain white cream thus formulated had pH 2.4, and contained 5% ing 5% N-(phosphonomethyl)-creatine was formulated from N-(phosphonomethyl)-D-4-hydroxyphenylglycine. Under N-(phosphonomethyl)-creatine (5 g), water (30 ml), propy the same procedure, a white cream containing 10% lene glycol (10 ml), and hydrophilic ointment or oil-in-water N-(phosphonomethyl)-D-4-hydroxyphenylglycine was for emulsion (55 g). Under the same procedure, a white cream mulated from N-(phosphonomethyl)-D-4-hydroxyphenylg containing 10% N-(phosphonomethyl)-creatine was formu lycine (10 g), water (10 ml), propylene glycol (20 ml), and lated from N-(phosphonomethyl)-creatine (10 g), water (30 hydrophilic ointment (60 g). ml), propylene glycol (10 ml), and hydrophilic ointment 0117. A male subject, age 86, had chronic plaque psoria (oil-in-water emulsion, 50 g). sis with erythema, moderately thick and silvery scales. The 0.124. A male subject, age 86, had chronic plaque pso subject topically applied twice daily the above white cream riasis with erythema, moderately thick and silvery scales. containing 10% N-(phosphonomethyl)-D-4-hydroxyphe The subject topically applied twice daily the above white nylglycine to one psoriatic lesion for two weeks. At the end cream containing 5% N-(phosphonomethyl)-creatine to one of two weeks, the erythema and silvery scales improved very psoriatic lesion for two weeks. At the end of two weeks, the substantially, and the treated skin had 70% improvement in erythema and silvery scales improved substantially, and the contrast to the untreated or vehicle control as judged by treated skin had 50% improvement in contrast to the clinical evaluation. untreated or vehicle control as judged by clinical evaluation. US 2007/01 6 1543 A1 Jul. 12, 2007

EXAMPLE 1.8 treated skin had 50% improvement in contrast to the 0125. A male subject, age 74, having itchy eczema on his untreated or vehicle control as judged by clinical evaluation. left leg, topically applied 7% N-(phosphonomethyl)-creatine 0133) EXAMPLE 21 cream prepared according to Example 17. The itch disap 0.134 N-(phosphonomethyl)-DL-asparagine (5 g) was peared within a few minutes after the topical application. dissolved in (95 ml) of a solution prepared from water (40 The treated skin did not itch for the next 8 hours. Thera parts by Volume), ethanol (40 parts by Volume) and propy peutic evaluation was judged to be 100% effective in con lene glycol (20 parts by volume). The composition thus trast to the untreated or vehicle control for immediate relief prepared had 2.7, and contained 5% N-(phosphonomethyl)- of itch. DL-asparagine in solution. 0126 The above results show that a representative 0.135 A male subject, age 36, who had hyperpigmented N-(phosphonomethyl)-amino acid would be therapeutically dark skin, topically applied the above 5% N-(phosphonom effective for topical treatment of disturbed keratinization and ethyl)-DL-asparagine Solution to an involved skin site once inflammatory conditions including erythema, eczema, der every other day with occlusion for ten days. After seven days matitis, dermatoses, itch, psoriasis, acne and rosacea. of topical application, the treated site had mild depigmen tation and showed lighter skin color as compared to EXAMPLE 19 untreated skin site. The treated site was 25% lighter in skin color as judged by clinical evaluation. After ten days of 0127 N-(phosphonomethyl)-creatine (2 g) was dissolved topical application, the treated site had substantial reduction in (98 ml) of a solution prepared from water (40 parts by in skin pigmentation. The treated site was 50% lighter in Volume), ethanol (40 parts by Volume) and propylene glycol skin color in contrast to the untreated or vehicle control as (20 parts by volume). The composition thus prepared had pH 2.5 and contained 2% N-(phosphonomethyl)-creatine in judged by clinical evaluation. Solution. 0.136 The above results show that a representative N-(phosphonomethyl)-amino acid would be effective for 0128 N-(phosphonomethyl)-creatine (5 g) was dissolved topical treatment of hyperpigmented skin, age spots, in (95 ml) solution prepared from water (40 parts by melasma, lentigines, mottled skin, aging related skin Volume), ethanol (40 parts by Volume) and propylene glycol changes, and would be topically effective for skin lighten (20 parts by Volume). The composition thus prepared con 1ng. tained 5% N-(phosphonomethyl)-creatine in solution. 0129. A male subject, age 35, who had X-linked ichthyo EXAMPLE 22 sis having thick and rough skin with adherent scales, topi 0.137. A male subject, age 36, who had X-linked ichthyo cally applied the above 5% N-(phosphonomethyl)-creatine sis having thick and rough skin with adherent scales, topi solution to an involved skin site once every other with cally applied the 5% N-(phosphonomethyl)-DL-asparagine occlusion for two weeks. After 10 days of topical applica Solution prepared according to Example 21 to an involved tion, most adherent scales disappeared and the skin had 50% skin site once every other day under occlusion for three improvement in contrast to the untreated or vehicle control weeks. After one week of topical application, most adherent as judged by clinical evaluation. After two weeks of topical scales disappeared and the treated site appeared Smooth. The application, the scales disappeared completely and the skin had 75% improvement in contrast to the untreated or treated skin became normal in appearance, and had 100% vehicle control as judged by clinical evaluation. After three improvement in contrast to the untreated or vehicle control weeks of topical application, the treated skin site appeared as judged by clinical evaluation. normal, and the skin had 100% improvement in contrast to 0130. The above results show that another representative the untreated or vehicle control as judged by clinical evalu N-(phosphonomethyl)-amino acid would be therapeutically ation. effective for topical treatment of disturbed keratinization and 0.138. The above results show that a representative hyperkeratotic conditions including dry skin, severe dry N-(phosphonomethyl)-amino acid would be therapeutically skin, ichthyosis, calluses, keratoses, acne, rosacea, blem effective for topical treatment of disturbed keratinization and ished skin, psoriasis and age spots. hyperkeratotic conditions including dry skin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea, blem EXAMPLE 20 ished skin, psoriasis and age spots. 0131 N-(phosphonomethyl)-tyramine (5 g) was sus pended in warm propylene glycol (30 ml), and water (5 ml), EXAMPLE 23 and the mixture thus obtained was mixed with hydrophilic 0.139 N-(phosphonomethyl)-creatine (5 g) was dissolved ointment (oil-in-water emulsion, 60 g). The white cream in (95 ml) solution prepared from water (40 parts by thus formulated had pH 2.1 and contained 5% N-(phospho Volume), ethanol (40 parts by Volume) and propylene glycol nomethyl)-tyramine. (20 parts by volume). The composition thus prepared had pH 0132 A male subject, age 86, had chronic plaque pso 2.5 , and contained 5% N-(phosphonomethyl)-creatine in riasis with erythema, moderately thick and silvery scales. Solution. The subject topically applied twice daily the above white 0140. A male subject, age 36, who had hyperpigmented cream containing 5% N-(phosphonomethyl)-tyramine to one dark skin, topically applied the above 5% N-(phosphonom psoriatic lesion for two weeks. At the end of two weeks, the ethyl)-creatine solution to an involved skin site once every erythema and silvery scales improved substantially, and the other day with occlusion for two weeks. After seven days of US 2007/01 6 1543 A1 Jul. 12, 2007

topical application, the treated site had mild depigmentation EXAMPLE 26 and showed lighter skin color as compared to untreated skin site. The treated site was 25% lighter in skin color in contrast 0147 N-(phosphonomethyl)-L-glutamine (5 g) was dis to the untreated or vehicle control as judged by clinical solved in (95 ml) of a solution prepared from water (40 parts evaluation. After two weeks of topical application, the by volume), ethanol (40 parts by volume) and propylene treated site had very Substantial reduction in skin pigmen glycol (20 parts by Volume). The composition thus prepared tation. The treated site was 75% lighter in skin color in had pH 2.0, and contained 5% N-(phosphonomethyl)-L- contrast to the untreated or vehicle control as judged by glutamine in Solution. clinical evaluation. 0.148. A male subject, age 36, who had hyperpigmented dark skin, topically applied the above 5% N-(phosphonom 0141. The above results show that a representative ethyl)-L-glutamine Solution to an involved skin site once N-(phosphonomethyl)-amino acid would be effective for every other day with occlusion for two weeks. After two topical treatment of hyperpigmented skin, age spots, weeks of topical application, the treated site had substantial melasma, lentigines, mottled skin, aging related skin reduction in skin pigmentation. The treated site had 50% changes, and would be topically effective for skin lighten lighter in skin color in contrast to the untreated or vehicle 1ng. control as judged by clinical evaluation. EXAMPLE 24 0.149 The above result shows that another representative 0142 N-(phosphonomethyl)-glycinamide (5 g) was dis N-(phosphonomethyl)-amino acid would be effective for solved in (95 ml) of a solution prepared from water (40 parts topical treatment of hyperpigmented skin, age spots, by volume), ethanol (40 parts by volume) and propylene melasma, lentigines, mottled skin, aging related skin glycol (20 parts by Volume). The composition thus prepared changes, and would be topically effective for skin lighten had pH 2.5 , and contained 5% N-(phosphonomethyl)- 1ng. glycinamide in Solution. EXAMPLE 27 0143 A male subject, age 36, who had hyperpigmented 0150. A male subject, age 36, who had X-linked ichthyo dark skin, topically applied the above 5% N-(phosphonom sis having thick and rough skin with adherent scales, topi ethyl)-glycinamide Solution to an involved skin site once cally applied 5% N-(phosphonomethyl)-L-glutamine solu every other day with occlusion for two weeks. After seven days of topical application, the treated site had mild depig tion prepared according to Example 26 to an involved skin mentation and showed lighter skin color as compared to site once every other day for three weeks. After two weeks untreated skin site. The treated site was 25% lighter in skin of topical application, most scales disappeared and the color in contrast to the untreated or vehicle control as judged treated site felt nearly smooth, and the skin had 75% by clinical evaluation. After two weeks of topical applica improvement in contrast to the untreated or vehicle control tion, the treated site had substantial reduction in skin pig as judged by clinical evaluation. After three weeks of topical mentation. The treated site was 50% lighter in skin color in application, the treated site appeared normal, and the skin contrast to the untreated or vehicle control as judged by had 100% improvement in contrast to the untreated or clinical evaluation. vehicle control as judged by clinical evaluation. 0144. The above results show that another representative 0151. The above results show that another representative N-(phosphonomethyl)-amino acid derivative would be N-(phosphonomethyl)-amino acid would be therapeutically effective for topical treatment of hyperpigmented skin, age effective for topical treatment of disturbed keratinization and spots, melasma, lentigines, mottled skin, aging related skin hyperkeratotic conditions including dry skin, severe dry changes, and would be topically effective for skin lighten skin, ichthyosis, calluses, keratoses, acne, rosacea, blem 1ng. ished skin, psoriasis and age spots. EXAMPLE 28 EXAMPLE 25 0145 A male subject, age 36, who had X-linked ichthyo 0152 N-(phosphonomethyl)-tyramine (5 g) and concen sis having thick and rough skin with adherent scales, topi trated ammonium hydroxide solution (1 ml) were dissolved cally applied 5% N-(phosphonomethyl)-glycinamide solu in a solution (94 ml) prepared from water (40 parts by tion prepared according to Example 24 to an involved skin Volume), ethanol (40 parts by Volume) and propylene glycol site once every other day for three weeks. After one week of (20 parts by volume). The composition thus prepared had pH topical application, most adherent scales disappeared and 7.1 and contained 5% N-(phosphonomethyl)-tyramine in the treated site appeared smooth. The skin had 75% Solution. improvement in contrast to the untreated or vehicle control 0153. A male subject, age 36, who had X-linked ichthyo as judged by clinical evaluation. After three weeks of topical sis having thick and rough skin with adherent scales, topi application, the treated skin site appeared normal, and the cally applied the above 5% N-(phosphonomethyl)-tyramine skin had 100% improvement in contrast to the untreated or Solution to an involved skin site once every other day under vehicle control as judged by clinical evaluation. occlusion for a week. After one week of topical application, 0146 The above results show that another N-(phospho most adherent scales disappeared and the treated site nomethyl)-amino acid derivative would be therapeutically appeared smooth. The skin had 75% improvement in con effective for topical treatment of disturbed keratinization and trast to the untreated or vehicle control as judged by clinical hyperkeratotic conditions including dry skin, severe dry evaluation. skin, ichthyosis, calluses, keratoses, acne, rosacea, blem 0154) The above results show that another representative ished skin, psoriasis and age spots. N-(phosphonomethyl)-amino acid would be therapeutically US 2007/01 6 1543 A1 Jul. 12, 2007

effective for topical treatment of disturbed keratinization and EXAMPLE 32 hyperkeratotic conditions including dry skin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea, blem 0.163 N-(phosphonomethyl)-y-aminobutanoic acid (10 g) ished skin, psoriasis and age spots. was dissolved in water (20 ml) and propylene glycol (10 ml), and the solution thus obtained was mixed with hydrophilic ointment (oil-in-water emulsion, 60 g). The white cream EXAMPLE 29 thus formulated had pH 1.9 and contained 10% N-(phospho 0155 N-(phosphonomethyl)-glutamine (3 g) was dis nomethyl)-y-aminobutanoic acid. solved in (97 ml) of a solution prepared from water (80 parts by volume) and propylene glycol (20 parts by volume). The EXAMPLE 33 composition thus prepared had pH 2.0 and contained 3% 0.164 N-(phosphonomethyl)-L-glutathione (5 g) was dis N-(phosphonomethyl)-L-glutamine in solution. solved in (95 ml) of a warm solution prepared from water 0156 N-(phosphonomethyl)-L-glutamine (10 g) was dis (40 parts by volume), ethanol (40 parts by volume) and solved in warm water (20 ml) and propylene glycol (10 ml), propylene glycol (20 parts by Volume). The composition and the solution thus obtained was mixed with hydrophilic thus prepared had pH 2.3 and contained 5% N-(phospho ointment (oil-in-water emulsion, 60 g). The white cream nomethyl)-L-glutathione in Solution. thus formulated had pH 1.3 and contained 10% N-(phospho nomethyl)-L-glutamine. EXAMPLE 34 0157. A male subject, age 74, having itchy eczema on his 0.165 N-(phosphonomethyl)-L-cysteine (5 g) was dis left thigh, topically applied the above 10% N-(phosphonom solved in (95 ml) of a warm solution prepared from water ethyl)-glutamine. The itch disappeared within a few minutes (40 parts by volume), ethanol (40 parts by volume) and after the topical application. The treated skin did not itch for propylene glycol (20 parts by Volume). The composition the next 8 hours. Therapeutic evaluation was judged to be thus prepared had pH 2.7 and contained 5% N-(phospho 100% effective in contrast to the untreated or vehicle control nomethyl)-L-cysteine in solution. for immediate relief of itch. EXAMPLE 35 0158. The above results show that a representative 0166 N-(phosphonomethyl)-guanidinoacetic acid N-(phosphonomethyl)-amino acid would be therapeutically N-(phosphonomethyl)-glycocyamine, 1 g was dissolved in effective for topical treatment of disturbed keratinization and a solution (99 ml) prepared from water (80 parts by volume) inflammatory conditions including erythema, eczema, der and propylene glycol (20 parts by Volume). The composition matitis, dermatoses, itch, psoriasis, acne and rosacea. thus prepared had pH 2.1, and contained 1% N-(phospho nomethyl)-guanidinoacetic acid in solution. EXAMPLE 30 0159 N-(phosphonomethyl)-L-glutamine (6 g) was dis EXAMPLE 36 solved in warm water (40 ml), and the solution thus obtained 0.167 The following is a typical process for preparing a was mixed with hydrophilic ointment (oil-in-water emul composition comprising an N-(phosphonomethyl)-amino sion, 54 g). The white cream thus formulated had pH 1.5 and acid or derivative for oral administration. contained 6% N-(phosphonomethyl)-L-glutamine. 0168 N-(Phosphonomethyl)-glycine crystals were con verted to fine powder by grinding with mortar and pestle. EXAMPLE 31 Lilly(R) gelatin capsules size No. 1, were filled to the top with 0160 N-(phosphonomethyl)-L-glutamic acid (8 g) was N-(phosphonomethyl)-glycine powder without mixing with dissolved in water (20 ml) and propylene glycol (10 ml), and gelatin powder. Each capsule thus prepared contained 300 the solution thus obtained was mixed with hydrophilic mg N-(phosphonomethyl)-glycine. ointment (oil-in-water emulsion, 62 g). The white cream 0169. A subject can take orally one or two capsules per thus formulated had pH 2.4 and contained 8% N-(phospho day for systemic administration to alleviate or improve nomethyl)-L-glutamic acid. cosmetic conditions, or medical disorders, symptoms or 0.161. A male subject, age 86, had chronic plaque pso syndromes associated with the nervous, vascular, muscu riasis with erythema, moderately thick and silvery scales. loskeletal or cutaneous system, or others. The subject topically applied twice daily the above white cream containing 8% N-(phosphonomethyl)-L-glutamic EXAMPLE 37 acid to one psoriatic lesion for two weeks. At the end of two 0170 N-(Phosphonomethyl)-L-tyrosine crystals were weeks, the erythema and silvery scales improved Substan converted to fine powder by grinding with mortar and pestle. tially and the treated skin had 50% improvement in contrast Lilly(R) (gelatin capsules size No. 1, were filled to the top to the untreated or vehicle control as judged by clinical with N-(phosphonomethyl)-L-tyrosine powder without mix evaluation. ing with gelatin powder. Each capsule thus prepared con 0162 The above results show that another representative tained 120 mg N-(phosphonomethyl)-L-tyrosine. N-(phosphonomethyl)-amino acid derivative would be 0171 A subject can take orally one or two capsules per therapeutically effective for topical treatment of disturbed day for systemic administration to alleviate or improve keratinization and inflammatory conditions including cosmetic conditions, or medical disorders, symptoms or erythema, eczema, dermatitis, dermatoses, itch, psoriasis, syndromes associated with the nervous, vascular, muscu acne and rosacea. loskeletal or cutaneous system, or others. US 2007/01 6 1543 A1 Jul. 12, 2007

EXAMPLE 38 emulsion, 75 g). The white cream thus formulated had pH 1.8 and contained 5% N-(phosphonomethyl)-4-guanidi 0172 N-(Phosphonomethyl)-L-serine crystals were con nobutanoic acid. verted to fine powder by grinding with mortar and pestle. Lilly(R) gelatin capsules size No. 1, were filled to the top with 0180. It will be appreciated by those skilled in the art that N-(phosphonomethyl)-L-serine powder without mixing changes could be made to the embodiments described above with gelatin powder. Each capsule thus prepared contained without departing from the broad inventive concept thereof. 130 mg N-(phosphonomethyl)-L-serine. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to 0173 A subject can take orally one or two capsules per cover modifications within the spirit and scope of the present day for systemic administration to alleviate or improve invention as defined by the appended claims. cosmetic conditions, or medical disorders, symptoms or syndromes associated with the nervous, vascular, muscu We claim: loskeletal or cutaneous system, or others. 1. An N-(phosphonoalkyl)-amino acid, a related com pound or a derivative thereof, the N-(phosphonoalkyl)- EXAMPLE 39 amino acid, related compound or derivative thereof being in 0174 N-(Phosphonomethyl)-L-proline crystals were a form as a free acid, salt, partial salt, lactone, amide or ester, converted to fine powderby grinding with mortar and pestle. or in Stereoisomeric or non-stereoisomeric form, other than Lilly(R) gelatin capsules size No. 1, were filled to the top with N-(phosphonomethyl)-glycine or N.N-bis(phosphonom N-(phosphonomethyl)-L-proline powder without mixing ethyl)-glycine. with gelatin powder. Each capsule thus prepared contained 2. The compound of claim 1, selected from the group 150 mg N-(phosphonomethyl)-L-proline. consisting of N-(phosphonoalkyl)-proline and a compound or derivative thereof having the following formula: 0175. A subject can take orally one or two capsules per day for systemic administration to alleviate or improve cosmetic conditions, or medical disorders, symptoms or wherein R is H, an alkyl group having 1 to 19 carbon syndromes associated with the nervous, vascular, muscu atoms, an aryl group having 6 to 19 carbon atoms or an loskeletal or cutaneous system, or others. aralkyl group having 7 to 19 carbon atoms; and R can also carry —OH, -SH, —SCH. —NH, —NRR, EXAMPLE 40 —COR - NHCONH, -NHC(+NR)NH, imida Zole, pyrrolidine or other heterocyclic group; m is an 0176 N-(Phosphonomethyl)-creatinine (5 g) was dis integer from 0 to 5; R is a phosphonoalkyl group solved in 95 ml of a solution prepared from water (80 parts having a formula (HO)PO(CH), ; R is H or a by volume) and propylene glycol (20 parts by volume). The phosphonoalkyl group having a formula liquid composition thus prepared had pH 4.8 and contained (HO)PO(CH), ; n is an integer from 1 to 9; R is 5% N-(phosphonomethyl)-creatinine. This composition NH, or ORs, Rs is H, an alkyl group having 1 to 19 would be topically effective for treatment or prevention of carbon atoms, an aryl group having 6 to 19 carbon cosmetic conditions or medical disorders, symptoms or atoms or an aralkyl group having 7 to 19 carbonatoms; syndromes associated with nervous, vascular, musculoskel and the H attached to any carbon atom can be substi etal or cutaneous system, or others. tuted by I, F, Cl, Br, OH or an alkoxy group having 1 to 9 carbon atoms; and wherein the N-(phospho EXAMPLE 41 noalkyl)-amino acid, related compound or derivative thereof is in a form as a free acid, salt, partial salt, 0177 N-(Phosphonomethyl)-L-omithine (8 g) was dis lactone, amide or ester, or in a stereoisomeric or solved in 92 ml of a solution prepared from water (80 parts non-stereoisomeric form; provided that the compound by volume) and propylene glycol (20 parts by volume). The is not N-(phosphonomethyl)-glycine or N,N-bis(pho liquid composition thus prepared had pH 1.4 and contained sphonomethyl)-glycine. 8% N-(phosphonomethyl)-L-omithine. This composition 3. The compound of claim 1, wherein the compound is an would be topically effective for treatment or prevention of N-(phosphonoalkyl)-amino acid. cosmetic conditions or medical disorders, symptoms or 4. The compound of claim 1, wherein the phosphonoalkyl syndromes associated with nervous, vascular, musculoskel of the N-(phosphonoalkyl)-amino acid compound, related etal or cutaneous system, or others. compound or compound derived therefrom is selected from the group consisting of phosphonomethyl, phosphonoethyl, EXAMPLE 42 phosphonopropyl, phosphonoisopropyl, phosphonobutyl, 0178 N,N-Bis(phosphonomethyl)-glycine (2.5 g) was phosphonoisobutyl, phosphonopentyl, phosphonoisopentyl, dissolved in water (10 ml), and the solution thus obtained phosphonooctyl and phosphonoisooctyl. was mixed with hydrophilic ointment (oil-in-water emul 5. The compound of claim 4, wherein the phosphonoalkyl sion, 87.5 g). The white cream thus formulated had pH 1.3 of the N-(phosphonoalkyl)-amino acid compound, related and contained 2.5% N,N-bis(phosphonomethyl)-glycine. compound or compound derived therefrom is phosphonom ethyl. 6. The compound of claim 1, wherein the compound is an EXAMPLE 43 N-(phosphonomethyl)-amino acid. 0179 N-(phosphonomethyl)-4-guanidinobutanoic acid 7. The compound of claim 5, wherein the N-(phospho (5 g) was dissolved in water (20 ml), and the solution thus nomethyl)-amino acid in a form as a free acid, salt, partial obtained was mixed with hydrophilic ointment (oil-in-water salt, lactone, amide or ester, or in a stereoisomeric or US 2007/016.1543 A1 Jul. 12, 2007 non-stereoisomeric form, is selected from the group con ethyl)-asparagine, N-(phosphonomethyl)-asparaginamide, sisting of N-(phosphonomethyl)-alanine, N-(phosphonom N-(phosphonomethyl)-Y-aminobutanoic acid, N-(phospho ethyl)-arginine, N-(phosphonomethyl)-asparagine, nomethyl)-arginine, N-(phosphonomethyl)-argininamide, N-(phosphonomethyl)-aspartic acid, N-(phosphonomethyl)- N-(phosphonomethyl)-arginine ethyl ester, N-(phospho cysteine, N-(phosphonomethyl)-glutamic acid, N-(phospho nomethyl)-creatine, N-(phosphonomethyl)-creatinine, nomethyl)-glutamine, N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-cysteine, N-(phosphonomethyl)- N-(phosphonomethyl)-isoleucine, N-(phosphonomethyl)- glutamic acid, N-(phosphonomethyl)-glutamic acid diethyl leucine, N-(phosphonomethyl)-lysine, N-(phosphonom ester, N-(phosphonomethyl)-glutamine, N-(phosphonom ethyl)-methionine, N-(phosphonomethyl)-phenylalanine, ethyl)-glutaminamide, N-(phosphonomethyl)-glutamine N-(phosphonomethyl)-proline, N-(phosphonomethyl)- ethyl ester, N-(phosphonomethyl)-glutathione, N-(phospho serine, N-(phosphonomethyl)-threonine, N-(phosphonom nomethyl)-4-hydroxyphenylglycine, N-(phosphonomethyl)- ethyl)-tryptophan, N-(phosphonomethyl)-tyrosine and lysine, N-(phosphonomethyl)-lysinamide, N-(phosphonom N-(phosphonomethyl)-valine. ethyl)-lysine ethyl ester, N-(phosphonomethyl)-omithine, 8. The compound of claim 1, wherein the N-(phospho N-(phosphonomethyl)-proline, N-(phosphonomethyl)-proli noalkyl)-amino acid compound, related compound or com namide, N-(phosphonomethyl)-proline ethyl ester, pound derived therefrom in a form as a free acid, salt, partial N-(phosphonomethyl)-proline propyl ester, N-(phospho salt, lactone, amide or ester, or in stereoisomeric or non nomethyl)-proline isopropyl ester, N-(phosphonomethyl)- stereoisomeric form, is selected from the group consisting of serine, N-(phosphonomethyl)-tyrosine and N-(phospho N-(phosphonomethyl)-3-alanine, N-(phosphonomethyl)-Y- nomethyl)-tyramine. aminobutanoic acid, N-(phosphonomethyl)-f-aminoisobu 10. A composition comprising an N-(phosphonoalkyl)- tanoic acid, N-(phosphonomethyl)-anserine, N-(phospho amino acid, a related compound or a derivative thereof, the nomethyl)-aminolevulinic acid, N-(phosphonomethyl)- N-(phosphonoalkyl)-amino acid, related compound or camosine, N-(phosphonomethyl)-canaline, derivative thereof being in a form as a free acid, salt, partial N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)- salt, lactone, amide or ester, or in stereoisomeric or non citrulline, N-(phosphonomethyl)-creatine, N-(phosphonom stereoisomeric form, and a cosmetically or pharmaceutically ethyl)-creatinine, N-(phosphonomethyl)-cysteine sulfinic acceptable vehicle for topical or systemic administration to acid, N-(phosphonomethyl)-cystine, N-(phosphonomethyl)- a mammalian subject. cycloserine, N-(phosphonomethyl)-dopaN-(phosphonom 11. The composition of claim 10, wherein the related ethyl)-3,4-dihydroxyphenylalanine), N-(phosphonomethyl)- compound or derivative is an N,N-bis(phosphonoalkyl)- dopamine (hydroxytyramine), N-(phosphonomethyl)- amino acid or an N,N'-bis(phosphonoalkyl)-amino acid. ethionine, N-(phosphonomethyl)-glutathione, 12. The composition of claim 11, wherein the related N-(phosphonomethyl)-guanidinoacetic acid, N-(phospho compound or derivative is an N,N-bis(phosphonomethyl)- nomethyl)-3-guanidinopropanoic acid, N-(phosphonom amino acid or an N,N'-bis(phosphonomethyl)-amino acid. ethyl)-4-guanidinobutanoic acid, N-(phosphonomethyl)-ho 13. The composition of claim 12, wherein the N.N- mocarnosine, N-(phosphonomethyl)-homocysteine, bis(phosphonomethyl)-amino acid or N,N'-bis(phospho N-(phosphonomethyl)-homoserine, N-(phosphonomethyl)- nomethyl)-amino acid in a form as a free acid, salt, partial 4-hydroxyphenylglycine, N-(phosphonomethyl)-hydroxy salt, lactone, amide or ester, or in stereoisomeric or non glutamic acid, N-(phosphonomethyl)-hydroxylysine, stereoisomeric form, is selected from the group consisting of N-(phosphonomethyl)-hydroxyproline, N-(phosphonom N,N-bis(phosphonomethyl)-alanine; N,N-bis(phosphonom ethyl)-hypusine, N-(phosphonomethyl)-homoarginine, ethyl)-arginine; N.N-bis(phosphonomethyl)-aspartic acid: N-(phosphonomethyl)-homocitrulline, N-(phosphonom N,N-bis(phosphonomethyl)-asparagine; N,N-bis(phospho ethyl)-homocystine, N-(phosphonomethyl)-homophenylala nomethyl)-cysteine; N.N-bis(phosphonomethyl)-glycine; nine, N-(phosphonomethyl)-homotryptophan, N-(phospho N,N-bis(phosphonomethyl)-glutamic acid: N,N-bis(pho nomethyl)-hydroxylysine, N-(phosphonomethyl)- sphonomethyl)-glutamine; N.N-bis(phosphonomethyl)-his hydroxyarginine, N-(phosphonomethyl)- tidine: N,N-bis(phosphonomethyl)-isoleucine; N.N-bis hydroxyhomoarginine, N-(phosphonomethyl)- (phosphonomethyl)-leucine; N.N-bis(phosphonomethyl)- hydroxycitrulline, N-(phosphonomethyl)-hydroxyomithine, lysine; N,N-bis(phosphonomethyl)-methionine; N.N- N-(phosphonomethyl)-hydroxyvaline, N-(phosphonom bis(phosphonomethyl)-phenylalanine; N,N- ethyl)-indospicine, N-(phosphonomethyl)-methoxinine, bis(phosphonomethyl)-serine; N.N-bis(phosphonomethyl)- N-(phosphonomethyl)-methylarginine, N-(phosphonom threonine; N,N-bis(phosphonomethyl)-tryptophan; N.N- ethyl)-methylhistidine, N-(phosphonomethyl)-methyllysine, bis(phosphonomethyl)-tyrosine; N,N- N-(phosphonomethyl)-methylornithine, N-(phosphonom bis(phosphonomethyl)-valine; N.N'-bis(phosphonomethyl)- ethyl)-methylserine, N-(phosphonomethyl)-norvaline, arginine; N,N'-bis(phosphonomethyl)-histidine; N,N'- N-(phosphonomethyl)-omithine, N-(phosphonomethyl)-OX bis(phosphonomethyl)-lysine and N,N'- alysine, N-(phosphonomethyl)-penicillamine (N-phospho bis(phosphonomethyl)-tryptophan. nomethyl-dimethylcysteine), N-(phosphonomethyl)-phe 14. The composition of claim 12, wherein the related nylglycine, N-(phosphonomethyl)-3-phenylserine, compound or compound derived therefrom in a form as a N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N- free acid, salt, partial salt, lactone, amide or ester, or in methyl-glycine). N-(phosphonomethyl)-serotonin stereoisomeric or non-stereoisomeric form, is selected from (N-phosphonomethyl-hydroxytryptamine), N-(phospho the group consisting of N.N-bis(phosphonomethyl)-3-ala nomethyl)-taurine, N-(phosphonomethyl)-tryptamine and nine; N.N-bis(phosphonomethyl)-Y-aminobutanoic acid: N-(phosphonomethyl)-tyramine. N,N-bis(phosphonomethyl)-B-aminoisobutanoic acid: N,N- 9. The compound of claim 1, wherein the compound is bis(phosphonomethyl)-anserine; N,N-bis(phosphonom selected from the group consisting of N-(phosphonom ethyl)-aminolevulinic acid: N,N-bis(phosphonomethyl)- US 2007/01 6 1543 A1 Jul. 12, 2007

camosine; N.N-bis(phosphonomethyl)-canaline; having a formula (HO)PO(CH), ; R is H or a bis(phosphonomethyl)-canavanine; phosphonoalkyl group having a formula bis(phosphonomethyl)-citrulline; (HO)PO(CH), ; n is an integer from 1 to 9; R is bis(phosphonomethyl)-creatine; NH, or ORs, R. is H, an alkyl group having 1 to 19 bis(phosphonomethyl)-creatinine; carbon atoms, an aryl group having 6 to 19 carbon bis(phosphonomethyl)-cysteine Sulfinic acid; atoms or an aralkyl group having 7 to 19 carbonatoms; bis(phosphonomethyl)-cystine; N.N-bis(phosphonomet and the H attached to any carbon atom can be substi cycloserine; N.N-bis(phosphonomethyl)-dopa (3: tuted by I, F, Cl, Br, OH or an alkoxy group having 1 bis(phosphonomethyl)-4-dihydroxyphenylalanine); to 9 carbon atoms; and wherein the N-(phospho bis(phosphonomethyl)-dopamine (hydroxytyramine); noalkyl)-amino acid, related compound or derivative bis(phosphonomethyl)-ethionine; thereof is in a form as a free acid, salt, partial salt, bis(phosphonomethyl)-glutathione; lactone, amide or ester, or in Stereoisomeric or non bis(phosphonomethyl)-guanidinoacetic acid; stereoisomeric form. bis(phosphonomethyl)-3-guanidinopropanoic acid; 16. The composition of claim 10, wherein the phospho bis(phosphonomethyl)-4-guanidinobutanoic acid; noalkyl of the N-(phosphonoalkyl)-amino acid compound, bis(phosphonomethyl)-homocamosine; related compound or compound derived therefrom is bis(phosphonomethyl)-homocysteine; selected from the group consisting of phosphonomethyl, bis(phosphonomethyl)-homoserine; phosphonoethyl, phosphonopropyl, phosphonoisopropyl. bis(phosphonomethyl)-4-hydroxyphenylglycine; phosphonobutyl, phosphonoisobutyl, phosphonopentyl, bis(phosphonomethyl)-hydroxyglutamic acid; phosphonoisopentyl, phosphonooctyl and phosphonoisooc bis(phosphonomethyl)-hydroxylysine; tyl. bis(phosphonomethyl)-hydroxyproline; 17. The composition of claim 10, wherein the compound bis(phosphonomethyl)-hypusine; is an N-(phosphonoalkyl)-amino acid. bis(phosphonomethyl)-homoarginine; 18. The composition of claim 10, wherein the compound bis(phosphonomethyl)-homocitrulline; is an N-(phosphonomethyl)-amino acid. bis(phosphonomethyl)-homocystine; bis(phosphonomethyl)-homophenylalanine; 19. The composition of claim 18, wherein the bis(phosphonomethyl)-homotryptophan; N-(phosphonomethyl)-amino acid in a form as a free acid, bis(phosphonomethyl)-hydroxylysine; salt, partial salt, lactone, amide or ester, or in a stereoiso bis(phosphonomethyl)-hydroxyarginine; meric or non-stereoisomeric form, is selected from the group bis(phosphonomethyl)-hydroxyhomoarginine; consisting of N-(phosphonomethyl)-alanine, N-(phospho bis(phosphonomethyl)-hydroxycitrulline; nomethyl)-arginine, N-(phosphonomethyl)-asparagine, bis(phosphonomethyl)-hydroxyomithine; N-(phosphonomethyl)-aspartic acid, N-(phosphonomethyl)- bis(phosphonomethyl)-hydroxyvaline; cysteine, N-(phosphonomethyl)-glutamic acid, N-(phospho bis(phosphonomethyl)-indospicine; nomethyl)-glutamine, N-(phosphonomethyl)-glycine, bis(phosphonomethyl)-methoxinine; N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-iso bis(phosphonomethyl)-methylarginine; leucine, N-(phosphonomethyl)-leucine, N-(phosphonom bis(phosphonomethyl)-methylhistidine; ethyl)-lysine, N-(phosphonomethyl)-methionine, bis(phosphonomethyl)-methylysine; N-(phosphonomethyl)-phenylalanine, N-(phosphonom bis(phosphonomethyl)-methylornithine; ethyl)-proline, N-(phosphonomethyl)-serine, N-(phospho bis(phosphonomethyl)-methylserine; nomethyl)-threonine, N-(phosphonomethyl)-tryptophan, bis(phosphonomethyl)-norvaline; N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)- bis(phosphonomethyl)-Omithine; valine. bis(phosphonomethyl)-oxalysine; 20. The composition of claim 10, wherein the bis(phosphonomethyl)-penicillamine (N-phosphonomethyl N-(phosphonoalkyl)-amino acid compound, related com dimethylcysteine); N,N-bis(phosphonomethyl)- pound or compound derived therefrom in a form as a free phenylglycine; N.N-bis(phosphonomethyl)-3-phenylserine; acid, salt, partial salt, lactone, amide or ester, or in Stereoi N,N-bis(phosphonomethyl)-sarcosine (N-phosphonom Someric or non-stereoisomeric form, is selected from the ethyl-N-methyl-glycine); N,N-bis(phosphonomethyl)-sero group consisting of N-(phosphonomethyl)-3-alanine, tonin (N-phosphonomethyl-hydroxytryptamine); N,N-bis N-(phosphonomethyl)-y-aminobutanoic acid, N-(phospho (phosphonomethyl)-taurine; N.N-bis(phosphonomethyl)- nomethyl)-3-aminoisobutanoic acid, N-(phosphonomethyl)- tryptamine; N.N-bis(phosphonomethyl)-tyramine and N,N'- anserine, N-(phosphonomethyl)-aminolevulinic acid, bis(phosphonomethyl)-Omithine. N-(phosphonomethyl)-camosine, N-(phosphonomethyl)- canaline, N-(phosphonomethyl)-canavanine, N-(phospho 15. The composition of claim 10, wherein the nomethyl)-citrulline, N-(phosphonomethyl)-creatine, N-(phosphonoalkyl)-amino acid, related compound or N-(phosphonomethyl)-creatinine, N-(phosphonomethyl)- derivative thereof has the following formula: cysteine Sulfinic acid, N-(phosphonomethyl)-cystine, N-(phosphonomethyl)-cycloserine, N-(phosphonomethyl)- wherein R is H, an alkyl group having 1 to 19 carbon dopaN-(phosphonomethyl)-3,4-dihydroxyphenylalanine). atoms, an aryl group having 6 to 19 carbon atoms or an N-(phosphonomethyl)-dopamine (hydroxytyramine), aralkyl group having 7 to 19 carbon atoms; and R can N-(phosphonomethyl)-ethionine, N-(phosphonomethyl)- also carry —OH, -SH, —SCH. —NH, —NRR, glutathione, N-(phosphonomethyl)-guanidinoacetic acid, - COR - NHCONH, -NHC(=NR)NH, imida N-(phosphonomethyl)-3-guanidinopropanoic acid, Zole, pyrrolidine or other heterocyclic group; m is an N-(phosphonomethyl)-4-guanidinobutanoic acid, integer from 0 to 5; R is a phosphonoalkyl group N-(phosphonomethyl)-homocamosine, N-(phosphonom US 2007/01 6 1543 A1 Jul. 12, 2007 20 ethyl)-homocysteine, N-(phosphonomethyl)-homoserine, anti-acne agents; anti-bacterial agents; anti-yeast agents; N-(phosphonomethyl)-4-hydroxyphenylglycine, anti-fungal agents; anti-viral agents; anti-infective agents; N-(phosphonomethyl)-hydroxyglutamic acid, N-(phospho anti-dandruff agents; anti-dermatitis agents; anti-eczema nomethyl)-hydroxylysine, N-(phosphonomethyl)-hydrox agents; anti-histamine agents; anti-pruritic agents; anti yproline, N-(phosphonomethyl)-hypusine, N-(phosphonom emetics; anti-motion sickness agents; anti-inflammatory ethyl)-homoarginine, N-(phosphonomethyl)- agents; anti-hyperkeratotic agents; antiperspirants; anti-pso homocitrulline, N-(phosphonomethyl)-homocystine, N-(phosphonomethyl)-homophenylalanine, N-(phospho riatic agents; anti-rosacea agents; anti-seborrheic agents; nomethyl)-homotryptophan, N-(phosphonomethyl)-hy hair conditioners and hair treatment agents; anti-aging and droxylysine, N-(phosphonomethyl)-hydroxyarginine, anti-wrinkle agents; anti-anxiety agents; anti-convulsant N-(phosphonomethyl)-hydroxyhomoarginine, N-(phospho agents; anti-depressant agents; Sunblock and Sunscreen nomethyl)-hydroxycitrulline, N-(phosphonomethyl)-hy agents, skin lightening agents; depigmenting agents; astrin droxyomithine, N-(phosphonomethyl)-hydroxyvaline, gents; cleansing agents; corn, callus or wart removing N-(phosphonomethyl)-indospicine, N-(phosphonomethyl)- agents, skin plumping agents; skin Volumizing agents; skin methoxinine, N-(phosphonomethyl)-methylarginine, firming agents; matrix metalloproteinase (MMP) inhibitors: N-(phosphonomethyl)-methylhistidine, N-(phosphonom topical cardiovascular agents; wound-healing agents; gum ethyl)-methyllysine, N-(phosphonomethyl)-methylorni disease or oral care agents; amino acids; peptides; dipep thine, N-(phosphonomethyl)-methylserine, N-(phospho tides; tripeptides; glutathione and its derivatives; oligopep nomethyl)-norvaline, N-(phosphonomethyl)-ornithine, tides; polypeptides; carbohydrates; aminocarbohydrates; N-(phosphonomethyl)-oxalysine, N-(phosphonomethyl)- Vitamins; corticosteroids; tanning agents; hormones and penicillamine (N-phosphonomethyl-dimethylcysteine), retinoids. N-(phosphonomethyl)-phenylglycine, N-(phosphonom 24. The composition of claim 22, wherein the cosmetic, ethyl)-3-phenylserine, N-(phosphonomethyl)-sarcosine pharmaceutical or other topically active agent as stated or as (N-phosphonomethyl-N-methyl-glycine), N-(phosphonom free base, free acid, ester, amide, lactone or salt form is ethyl)-serotonin (N-phosphonomethyl-hydroxytryptamine), selected from the group consisting of abacavir, abciximab, N-(phosphonomethyl)-taurine, N-(phosphonomethyl)- acamprosate, acarbose, acebutolol, acetaminophen, acetami tryptamine and N-(phosphonomethyl)-tyramine. noSalol, acetazolamide, acetic acid, acetohydroxamic acid, N-acetylcysteine and its esters, N-acetylglutathione and its 21. The composition of claim 10, wherein the esters, acitretin, aclometaSone dipropionate, acrivastine, N-(phosphonoalkyl)-amino acid compound, related com acthrel, actidose, actigall, acyclovir, adalimumab, ada pound or compound derived therefrom in a form as a free palene, adefovir dipivoxil, adenosine, agallsidase, albenda acid, salt, partial salt, lactone, amide or ester, or in Stereoi Zole, albumin, albuterol, aldesleukin, alefacept, alemtu Someric or non-stereoisomeric form, is selected from the Zumab, alendronate, alfuZosin, alitretinoin, allantoin, allium, group consisting of N-(phosphonomethyl)-asparagine, allopurinol, alloxanthine, almotriptan, alosetron, alpha toco N-(phosphonomethyl)-asparaginamide, N-(phosphonom pheral, alpha-proteinase, alprazolam, alprenolol, alpros ethyl)-y-aminobutanoic acid, N-(phosphonomethyl)-argin tadil, alteplase, altretamine, aluminum acetate, aluminum ine, N-(phosphonomethyl)-argininamide, N-(phosphonom chloride, aluminum chlorohydroxide, aluminum hydroxide, ethyl)-arginine ethyl ester, N-(phosphonomethyl)-creatine, amantadine, amifostine, amiloride, aminacrine, amino acid, N-(phosphonomethyl)-creatinine, N-(phosphonomethyl)- aminobenzoate, p-aminobenzoic acid, aminocaproic acid, cysteine, N-(phosphonomethyl)-glutamic acid, N-(phospho aminohippurate, aminolevulinic acid, aminosalicylic acid, nomethyl)-glutamic acid diethyl ester, N-(phosphonom amiodarone, amitriptyline, amlodipine, amocarzine, amodi ethyl)-glutamine, N-(phosphonomethyl)-glutaminamide, aquin, amorolfine, amoxapine, amoxicillin, amphetamine, N-(phosphonomethyl)-glutamine ethyl ester, N-(phospho amphotericin, amplicillin, amprenavir, anagrelide, anakinra, nomethyl)-glutathione, N-(phosphonomethyl)-glycine, anastroZole, anisindione, anthralin, antihemophilic, anti N-(phosphonomethyl)-glycinamide, N-(phosphonomethyl)- thrombin, anti-thymocyte, antivenin, apomorphine, aprepi glycine ethyl ester, N-(phosphonomethyl)-glycine propyl tant, aprotinin, arbutin, argatroban, aripiprazole, arnica, ester, N-(phosphonomethyl)-glycine isopropyl ester, ascorbic acid and its esters, ascorbyl palmitate, aspirin, N-(phosphonomethyl)-4-hydroxyphenylglycine, atazanavir, atenolol, atomoxetine, atorvastatin, atovaquone, N-(phosphonomethyl)-lysine, N-(phosphonomethyl)-lysina atropine, azathioprine, azelaic acid, azelastine, azithromy mide, N-(phosphonomethyl)-lysine ethyl ester, N-(phospho cin, baclofen, bacitracin, balsalazide, balsam, basiliximab, nomethyl)-omithine, N-(phosphonomethyl)-proline, beclomethasone dipropionate, bemegride, benazepril, ben N-(phosphonomethyl)-prolinamide, N-(phosphonomethyl)- droflumethiazide, benzocaine, benzonatate, benzophenone, proline ethyl ester, N-(phosphonomethyl)-proline propyl benzoyl peroxide, benztropine, bepridil, beta carotene, ester, N-(phosphonomethyl)-proline isopropyl ester, betamethasone dipropionate, betamethasone Valerate, betax N-(phosphonomethyl)-serine, N-(phosphonomethyl)-ty olol, bethanechol, bevacizumab, bexarotene, bicalutamide, rosine and N-(phosphonomethyl)-tyramine. bimatoprost, bioflavonoids, biotin, biperiden, bisacodyl, 22. The composition of claim 10, wherein the composi bisoprolol, bivalirudin, bortezomib, bosentan, botulinum, tion further comprises a cosmetic, pharmaceutical or other brimonidine, brinzolamide, bromocriptine, bromphe topically active agent. niramine, budesonide, bumetanide, bupivacaine, buprenor 23. The composition of claim 22, wherein the cosmetic, phine, bupropion, burimamide, buspirone, buSulfan, but pharmaceutical or other topically active agent is selected abarbital, butalbital, butenafine, butoconazole, butorphanol, from the group consisting of hydroxyacids, ketoacids and butyl aminobenzoate, cabergoline, caffeic acid, caffeine, related compounds; phenyl alpha acyloxyalkanoic acids and calcipotriene, calcitonin-Salmon, calcitriol, calfactant, derivatives; N-acyl-aldosamines, N-acylamino acids and camelia sinensis, camphor, candesartan cilexetil, capecit related N-acyl compounds; local analgesics and anesthetics; abine, capreomycin, capsaicin, captopril, carbamazepine, US 2007/01 6 1543 A1 Jul. 12, 2007 carbamide peroxide, carbidopa, carbinoxamine, cefditoren naproxen, nefazodone, nelfinavir, neomycin, nevirapine, pivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetiriz nicardipine, nicotine, nifedipine, nimodipine, nisoldipine, ine, cevimeline, chitosan, chlordiazepoxide, chlorhexidine, nitrofurantoin, nizatidine, norepinephrine, nystatin, octo chloroquine, chlorothiazide, chloroxylenol, chlorphe pamine, octreotide, octyl methoxycinnamate, octyl salicy niramine, chlorpromazine, chlorpropamide, ciclopiroX, cil late, ofloxacin, olanzapine, olmesartan medoxomil, olopata ostaZol, cimetidine, cinacalcet, ciprofloxacin, citalopram, dine, omeprazole, ondansetron, oxiconazole, oxotremorine, citric acid, cladribine, clarithromycin, clemastine, clindamy oxybenzone, oxybutynin, oxycodone, oxymetazoline, padi cin, clioquinol, clobetasol propionate, clocortolone pivalate, mate O, palonosetron, pantothenic acid, pantoyl lactone, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine, paroxetine, pemoline, penciclovir, penicillamine, penicil coal tar, coal tar extracts (LCD), codeine, cromolyn, crota lins, pentazocine, pentobarbital, pentostatin, pentoxifylline, miton, cyclizine, cyclobenzaprine, cycloserine, cytarabine, pergolide, perindopril, permethrin, phencyclidine, dacarbazine, dalfopristin, dapsone, daptomycin, daunorubi phenelZine, pheniramine, phenmetrazine, phenobarbital, cin, deferoxamine, dehydroepiandrosterone, delavirdine, phenol, phenoxybenzamine, phentolamine, phenylephrine, desipramine, desloratadine, desmopressin, desoximetaSone, phenylpropanolamine, phenytoin, physostigmine, pilo dexamethasone, dexmedetomidine, dexmethylphenidate, carpine, pimecrolimus, pimozide, pindolol, pioglitaZone, dexraZoxane, dextroamphetamine, diazepam, diclofenac, pipamazine, piperonyl butoxide, pirenzepine, podofilox, dicyclomine, didanosine, dihydrocodeine, dihydromor poVidone iodine, pramipexole, pramoxine, praZosin, pred phine, diltiazem, 6,8-dimercaptooctanoic acid (dihydroli nisone, prenalterol, prilocaine, procainamide, procaine, pro poic acid), diphenhydramine, diphenoxylate, dipyridamole, carbazine, promazine, promethazine, promethazine propi disopyramide, dobutamine, dolfetilide, dolasetron, done Onate, propafenone, propoxyphene, propranolol. pezil, dopa esters, dopamide, dopamine, dorzolamide, dox propylthiouracil, protriptyline, pseudoephedrine, pyrethrin, epin, doxorubicin, doxycycline, doxylamine, doxepin, pyrilamine, pyrimethamine, quetiapine, quinapril, quineth dulloxetine, dyclonine, econazole, efalizumab, eflomithine, aZone, quinidine, quinupristin, rabeprazole, reserpine, resor eletriptan, emitricitabine, enalapril, ephedrine, epinephrine, cinol, retinal, 13-cis retinoic acid, retinoic acid, retinol, epinine, epirubicin, eptifibatide, ergotamine, erythromycin, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid, escitalopram, esmolol, esomeprazole, estazolam, estradiol. ribonolactone, rifampin, rifapentine, rifaximin, riluzole, etanercept, ethacrynic acid, ethinyl estradiol, etidocaine, rimantadine, risedronic acid, risperidone, ritodrine, rivastig etomidate, famciclovir, famotidine, felodipine, fentanyl. mine, rizatriptan, ropinirole, ropivacaine, Salicylamide, Sali ferulic acid, fexofenadine, flecainide, fluconazole, flucy cylic acid, Salmeterol, Scopolamine, Selegiline, selenium tosine, fluocinolone acetonide, fluocinonide, 5-fluorouracil, Sulfide, serotonin, Sertaconazole, sertindole, Sertraline, shale fluoxetine, fluiphenazine, flurazepam, fluticaSone propionate, tar, Sibutramine, Sildenafil. Sotalol, Streptomycin, Strychnine, fluvoxamine, formoterol, furosemide, galactarolactone, Sulconazole, Sulfacetamide, Sulfabenz, Sulfabenzamide, Sul galactonic acid, galactonolactone, galantamine, gatifloxacin, fabromomethazine, Sulfacetamide (sodium Sulfacetamide), gefitinib, gemcitabine, gemifloxacin, glucarolactone, glu Sulfachlorpyridazine, Sulfacytine, Sulfadiazine, Sul conic acid, gluconolactone, glucuronic acid, glucuronolac fadimethoxine, Sulfadoxine, Sulfaguanole, Sulfalene, Sul tone, glycolic acid, griseofulvin, guaifenesin, guanethidine, famethizole, Sulfamethoxazole, Sulfanilamide, Sulfapyra N-guanylhistamine, haloperidol, haloprogin, hexylresorci Zine, Sulfapyridine, Sulfasalazine, Sulfasomizole, nol, homatropine, homosalate, hydralazine, hydrochlorothi Sulfathiazole, Sulfisoxazole, Sulfur, tacrolimus, tadalafil. azide, hydrocortisone, hydrocortisone 21-acetate, hydrocor tamsulosin, tartaric acid, tazarotene, tegaserod, tellithromy tisone 17-butyrate, hydrocortisone 17-valerate, hydrogen cin, telmisartan, temozolomide, tenofovir disoproxil, tera peroxide, hydromorphone, hydroquinone, hydroquinone Zosin, terbinafine, terbutaline, terconazole, terfenadine, tet monoether, hydroxy Zine, hyoscyamine, hypoxanthine, ibu racaine, tetracycline, tetrahydrozoline, thalidomide, profen, ichthammol. idarubicin, imatinib, imipramine, imi theobromine, theophylline, thiabendazole, thioctic acid quimod, indinavir, indomethacin, infliximab, irbesartan, (lipoic acid), thioridazine, thiothixene, thymol, tiagabine, irinotecan, isoetharine, isoproterenol, itraconazole, kanamy timolol, tinidazole, tioconazole, tirofiban, tizanidine, tobra cin, ketamine, ketanserin, ketoconazole, ketoprofen, keto mycin, tocainide, tolazoline, tolbutamide, tolnaftate, toltero tifen, kojic acid, labetalol, lactic acid, lactobionic acid, dine, tramadol, tranylcypromine, traZodone, triamcinolone lamivudine, lamotrigine, lanSoprazole, letrozole, leuprolide, acetonide, triamcinolone diacetate, triamcinolone hexac levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, etonide, triamterene, triazolam, triclosan, triflupromazine, loratadine, loperamide, losartan, loxapine, lysergic diethy trimethoprim, trimipramine, tripelennamine, triprolidine, lamide, mafenide, malic acid, maltobionic acid, mandelic tromethamine, tropic acid, tyramine, undecylenic acid, urea, acid, maprotiline, mebendazole, mecamylamine, meclizine, urocanic acid, ursodiol, Valacyclovir, Vardenafil. Venlafax meclocycline, memantine, menthol, meperidine, mepiv ine, Verapamil, vitamin E acetate, Voriconazole, warfarin, acaine, meduinol, mercaptopurine, mescaline, metaneph wood tar, Xanthine, Zafirlukast, Zaleplon, Zinc pyrithione, rine, metaproterenol, metaraminol, metformin, methadone, Ziprasidone, Zolmitriptan and Zolpidem. methamphetamine, methotrexate, methoxamine, methyl 25. A method of alleviating or improving a condition, dopa esters, methyldopamide, 3.4-methylenedioxymetham disorder, symptom or syndrome associated with at least one phetamine, methylactic acid, methyl nicotinate, meth of a nervous, vascular, musculoskeletal or cutaneous system, ylphenidate, methyl salicylate, metiamide, metolaZone, the method comprising administering to a mammalian Sub metoprolol, metronidazole, mexiletine, miconazole, mida ject having the disorder, symptom or syndrome an amount Zolam, midodrine, miglustat, minocycline, minoxidil, mir effective for alleviating or improving the condition, disorder, tazapine, mitoxantrone, moexiprilat, molindone, monoben symptom or syndrome, of a composition comprising an Zone, morphine, moxifloxacin, moxonidine, mupirocin, N-(phosphonoalkyl)-amino acid, a related compound or a nadolol, naftifine, nalbuphine, nalmefene, naloxone, derivative thereof, the N-(phosphonoalkyl)-amino acid, US 2007/01 6 1543 A1 Jul. 12, 2007 22 related compound or derivative thereof being in a form as a leucine, N-(phosphonomethyl)-leucine, N-(phosphonom free acid, salt, partial salt, lactone, amide or ester, or in ethyl)-lysine, N-(phosphonomethyl)-methionine, Stereoisomeric or non-stereoisomeric form, and a cosmeti N-(phosphonomethyl)-phenylalanine, N-(phosphonom cally or pharmaceutically acceptable vehicle for topical or ethyl)-proline, N-(phosphonomethyl)-serine, N-(phospho systemic administration to the mammalian Subject. nomethyl)-threonine, N-(phosphonomethyl)-tryptophan, 26. The method of claim 25, wherein the mammalian N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)- Subject is a human. valine. 27. The method of claim 25, wherein the N-(phospho 33. The method of claim 25, wherein the N-(phospho noalkyl)-amino acid, related compound or derivative thereof noalkyl)-amino acid compound, related compound or com is an N-(phosphonomethyl)-amino acid, related compound pound derived therefrom in a form as a free acid, salt, partial or derivative thereof, as a free acid, salt, partial salt, lactone, salt, lactone, amide or ester, or in Stereoisomeric or non amide or ester. Stereoisomeric form, is selected from the group consisting of 28. The method of claim 25, wherein the N-(phospho N-(phosphonomethyl)-3-alanine, N-(phosphonomethyl)-y- noalkyl)-amino acid, related compound or derivative thereof aminobutanoic acid, N-(phosphonomethyl)-3-aminoisobu has the following formula: tanoic acid, N-(phosphonomethyl)-anserine, N-(phospho nomethyl)-aminolevulinic acid, N-(phosphonomethyl)- wherein R is H, an alkyl group having 1 to 19 carbon camosine, N-(phosphonomethyl)-canaline, atoms, an aryl group having 6 to 19 carbon atoms or an N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)- aralkyl group having 7 to 19 carbon atoms; and R can citrulline, N-(phosphonomethyl)-creatine, N-(phosphonom also carry —OH, -SH, —SCH. —NH, —NRR, ethyl)-creatinine, N-(phosphonomethyl)-cysteine Sulfinic —COR - NHCONH, -NHC(=NR)NH, imida acid, N-(phosphonomethyl)-cystine, N-(phosphonomethyl)- Zole, pyrrolidine or other heterocyclic group; m is an cycloserine, N-(phosphonomethyl)-dopaN-(phosphonom integer from 0 to 5; R is a phosphonoalkyl group ethyl)-3,4-dihydroxyphenylalanine, N-(phosphonomethyl)- having a formula (HO)PO(CH.) : dopamine (hydroxytyramine), N-(phosphonomethyl)- ethionine, N-(phosphonomethyl)-glutathione, R is H or a phosphonoalkyl group having a formula N-(phosphonomethyl)-guanidinoacetic acid, N-(phospho (HO)PO(CH), ; n is an integer from 1 to 9; nomethyl)-3-guanidinopropanoic acid, N-(phosphonom R is —NH or —ORs. Rs is H. an alkyl group having 1 ethyl)-4-guanidinobutanoic acid, N-(phosphonomethyl)-ho to 19 carbon atoms, an aryl group having 6 to 19 carbon mocamosine, N-(phosphonomethyl)-bomocysteine, atoms or an aralkyl group having 7 to 19 carbonatoms; N-(phosphonomethyl)-homoserine, N-(phosphonomethyl)- and the H attached to any carbon atom can be substi 4-hydroxyphenylglycine, N-(phosphonomethyl)-hydroxy tuted by I, F, Cl, Br, OH or an alkoxy group having 1 glutamic acid, N-(phosphonomethyl)-hydroxylysine, to 9 carbon atoms; and wherein the N-(phospho N-(phosphonomethyl)-hydroxyproline, N-(phosphonom noalkyl)-amino acid, related compound or derivative ethyl)-hypusine, N-(phosphonomethyl)-homoarginine, thereof is in a form as a free acid, salt, partial salt, N-(phosphonomethyl)-homocitrulline, N-(phosphonom lactone, amide or ester, or in Stereoisomeric or non ethyl)-homocystine, N-(phosphonomethyl)-homophenylala stereoisomeric form. nine, N-(phosphonomethyl)-homotryptophan, N-(phospho 29. The method of claim 25, wherein the phosphonoalkyl nomethyl)-hydroxylysine, N-(phosphonomethyl)- of the N-(phosphonoalkyl)-amino acid compound, related hydroxyarginine, N-(phosphonomethyl)- compound or compound derived therefrom is selected from hydroxyhomoarginine, N-(phosphonomethyl)- the group consisting of phosphonomethyl, phosphonoethyl, hydroxycitrulline, N-(phosphonomethyl)-hydroxyomithine, phosphonopropyl, phosphonoisopropyl, phosphonobutyl, N-(phosphonomethyl)-hydroxyvaline, N-(phosphonom phosphonoisobutyl, phosphonopentyl, phosphonoisopentyl, ethyl)-indospicine, N-(phosphonomethyl)-methoxinine, phosphonooctyl and phosphonoisooctyl. N-(phosphonomethyl)-methylarginine, N-(phosphonom 30. The method of claim 25, wherein the compound is an ethyl)-methylhistidine, N-(phosphonomethyl)-methyllysine, N-(phosphonoalkyl)-amino acid. N-(phosphonomethyl)-methylomithine, N-(phosphonom 31. The method of claim 30, wherein the compound is an ethyl)-methylserine, N-(phosphonomethyl)-norvaline, N-(phosphonomethyl)-amino acid. N-(phosphonomethyl)-omithine, N-(phosphonomethyl)-ox 32. The method of claim 31, wherein the N-(phospho alysine, N-(phosphonomethyl)-penicillamine (N-phospho nomethyl)-amino acid in a form as a free acid, salt, partial nomethyl-dimethylcysteine), N-(phosphonomethyl)-phe salt, lactone, amide or ester, or in a stereoisomeric or nylglycine, N-(phosphonomethyl)-3-phenylserine, non-stereoisomeric form, is selected from the group con N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N- sisting of N-(phosphonomethyl)-alanine, N-(phosphonom methyl-glycine), N-(phosphonomethyl)-serotonin ethyl)-arginine, N-(phosphonomethyl)-asparagine, (N-phosphonomethyl-hydroxytryptamine), N-(phospho N-(phosphonomethyl)-aspartic acid, N-(phosphonomethyl)- nomethyl)-taurine, N-(phosphonomethyl)-tryptamine and cysteine, N-(phosphonomethyl)-glutamic acid, N-(phospho N-(phosphonomethyl)-tyramine. nomethyl)-glutamine, N-(phosphonomethyl)-glycine, N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-iso k k k k k