AR052823A1 - USE OF A VITRONECTINE RECEIVER ANTAGONIST FOR THE PREPARATION OF A USEFUL PHARMACEUTICAL FORMULATION TO INHIBIT THE EXCESS OF SCARS FORMATION IN THE SKIN OF A MAMMER AND SUCH FORMULATION - Google Patents

USE OF A VITRONECTINE RECEIVER ANTAGONIST FOR THE PREPARATION OF A USEFUL PHARMACEUTICAL FORMULATION TO INHIBIT THE EXCESS OF SCARS FORMATION IN THE SKIN OF A MAMMER AND SUCH FORMULATION

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AR052823A1
AR052823A1 ARP050105363A ARP050105363A AR052823A1 AR 052823 A1 AR052823 A1 AR 052823A1 AR P050105363 A ARP050105363 A AR P050105363A AR P050105363 A ARP050105363 A AR P050105363A AR 052823 A1 AR052823 A1 AR 052823A1
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Argentina
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alkyl
cycloalkyl
het
halogen
group
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ARP050105363A
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Smithkline Beecham Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Birds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Uso de un antagonista del receptor de vitronectina para la preparacion de una formulacion farmacéutica util para inhibir el exceso de formacion de cicatrices en la piel de a un mamífero en necesidad del mismo por administracion topica. Dicha piel se ha cortado, agrietado, desgarrado o lesionado durante la curacion y la cicatrizacion excesiva puede ser hipertrofica. Dicho antagonista es un compuesto de formula (1) o (2), en la que: R es H, alquilo C1-6, Ar, Het o alquilarilo C1-6; R1 es R7, A- alquiloC0-4, A-alqueniloC2-4, A-alquiniloC2-4, A-oxoalqueniloC3-4, A-oxoalquiniloC3-4, A-aminoalquiloC1-4, A-aminoalqueniloC3-4 o A-aminoalquiniloC3-4, sin sustituir o sustituido con cualquier combinacion posible de uno o más de R10 o R7; A es H, cicloalquilo C3-6, Het o Ar; R7 es -COR8, -COCR'2R9, -C(S)R8, -S(O)mOR', -S(O)mNR'R'', -PO(OR'), -PO(OR')2, -NO2, o tetrazolilo; cada R8 es independientemente -OR', -NR'R'' -NR'SO2R', -NR'OR' o -OCR'2CO(O)R'; R9 es -OR', -CN, -S(O)rR', -S(O)mN(R')2, -C(O)R', C(O)N(R)2 o -CO2R'; R10 es H, halo, -OR11, -CN, -NR'R11 , -NO2, -CF3, CF3S(O)r-, CO2R', -CON(R')2, A-alquiloC0-6-, A-oxoalquiloC1-6-, A-alqueniloC2-6-, A-alquiniloC2-6-, A-alquiloxiC0-6-, A-alquilaminoC0-6- o A-alquilC0-6-S(O)r-; R11es R', - C(O)R', -C(O)N(R')2, -C(O)OR', -S(O)mR' o -S(O)mN(R')2; R2 es un grupo de formulas (3), W es -(CHRg)a-U-(CHRg)b-; U es ausente o es CO, CRg2, C(=CRg2), S(O)k, O, NRg, CRgORg, CRg(ORk)CRg2, CRg2CRg(ORk), C(O)CRg2, CRg2C(O), CONRi, NRiCO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2, N=N, NRgNRg, NRgCRg2, CRg2NRg, CRg2O, OCRg2, C:::C o CRg=CRg; G es NRe, S u O; Rg is H, alquilo C1-6, Het-alquiloC0-6, cicloalquilC3-7-alquiloC0-6 o Ar-alquiloC0-6; Rk es Rg, -C(O)Rg, o - C(O)ORf; Ri es H, alquilo C1-6, Het-alquiloC0-6, cicloalquilC3-7-alquiloC0-6, Ar-alquiloC0-6 o alquilo C1-6 sustituido con uno a tres grupos seleccionados entre el grupo que cosiste en halogeno, CN, NRg2, ORg, SRg, CO2Rg, y CON(Rg)2; Rf es H, alquilo C1-6 o Ar-alquiloC0-6; Re es H, alquilo C1-6, Ar-alquiloC0-6, Het-alquiloC0-6, cicloalquilC3-7-alquiloC0-6 o (CH2)kCO2Rg; Rb y Rc se seleccionan independientemente entre el grupo que consiste en H, alquilo C1-6, Ar-alquiloC0-6, Het-alquiloC0- 6, cicloalquilC3-6-alquiloC0-6, halogeno, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2, CO(NRf)2, y CH2N(Rf)2, o Rb y Rc se unen para formar un anillo carbocíclico o heterocíclico, aromático o no aromático de cinco o seis miembros, sin sustituir o sustituido con hasta tres sustituyentes seleccionados entre el grupo que consiste en halogeno, CF3, alquilo C1-4, ORf, S(O)kRf, CORf, CO2Rf, OH, NO2, N(Rf)2, CO(NRf)2, CH2N(Rf)2, y metilenodioxi; Q1, Q2, Q3 y Q4 son independientemente N o C-Ry, con la condicion de que no más de Q1, Q2, Q3 y Q4 sea N; R' es H, alquilo C1-6, Ar-alquiloC0-6 o cicloalquilC3-6-alquiloC0-6; R'' es R', -C(O)R' o -C(O)OR'; R''' es H, alquilo C1-6, Ar-alquiloC0-6, Het-alquiloC0-6, cicloalquilC3-6-alquiloC0-6, halogeno, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2, CO(NRf)2, o CH2N(Rf)2; Ry es H, halo, -OR9, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, CO2Rg, -COR9 o -CONRg2, o alquilo C1-6 sin sustituir o sustituido con halo, -ORg, -SRg, - CN, -NRgR'', -NO2, -CF3, R'S(O)r-, - CO2Rg, -CORg o -CONRg2; a es 0, 1 o 2; b es 0, 1 o 2; k es 0, 1 o 2; m es 1 o 2; r es 0, 1 o 2; s es 0, 1 o 2; u es 0 o 1; y v es 0 o 1; o un compuesto de formula (2), en la que A1 es C o N; E es un anillo heteroaromático de cinco o seis miembros o un anillo aromático de seis miembros sin sustituir o sustituido con R3* o R4*; X1-X2 es CHR1*-CH, CR1*=C, NR1*-CH, S(O)u*-CH o O-CH; X3 es CR5*R5'*, NR5*, S(O)u* u O; R* es H, alquilo C1-6, Ar, Het, alquilarilo C1-6; R''* es R'*, -C(O)R'* o - C(O)OR5*; R'''* es alquilo C1-6, cicloalquilC3-7-alquiloC0-4 o Ar-alquiloC0-4; R1* es H, alquilo C1-6, ciclalquilC3-7-alquiloC0-4 o Ar-alquiloC0-4; R2* es -OR'*, -NR'*R''*, -NR'*SO2R'''*, -NROR'*, -OC(R'*)2C(O)OR'*, -OC(R'*)2OC(O)-R'*, - OC(R'*)2C(O)N(R'*)2, CF3 o COC(R'*)2R2'*; R2'* es -OR'*, -CN, -S(O)r*R'*, S(O)2N(R'*)2, -C(O)R'*, C(O)N(R'*)2 o -CO2R'*; R5* y R5'* son independientemente H, alquilo C1-6, cicloalquilC3-7-alquiloC0-4 o Ar-alquiloC0-4; R6* es W-(C(R'*)2)q*-Z*- (CR'*R10*)r*-U*-(C(R'*)2)s*-V*- o W'*-(C(R'*)2)q*-U*-(C(R'*)2)s*-; R3*, R4* y R7* son independientemente H, halo, -OR12*, -SR12*. -CN, -NR'*R12*, -NO2, -CF3, CF3S(O)r*-, -CO2R'*, -CON(R1*)2, R14*-alquiloC0-6-, R14*-oxoalquiloC1-6, , R14*-alqueniloC2- 6-, R14*-alquiniloC2-6, R14*-alquiloxiC0-6-, R14*-CalquilaminoC0-6 o R14*-alquilC0-6-S(O)r*-; R8* es R'*, C(O)R'*, CN, NO2, SO2R'* o C(O)OR5*; R9* es R'*, -CF3, -SR'*, o -OR'*; R1O* es H, alquilo C1-4, o -NR'*R''*; R12* es R'*, -C(O)R'*, - C(O)N(R'*)2, -C(O)OR5*, -S(O)m*R'* o S(O)2N(R'*)2; R14* es H, cicloalquilo C3-6, Het o Ar; R15* es H, alquilo C1-10, cicloalquiloC3-7-alquiloC0-8 o Ar-alquiloC0-8; U* y V* están ausentes o son CO, C(R'*)2, C=C(R15*)2, S(O)n*, O, NR15*, CR15'*OR15*, CR'*(OR''*)CR'*2, CR'*2CR'*(OR''*), C(O)C(R'*)2, C(R15*)2C(O), CONR15*, NR15*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR15*, NR15*C(S), SO2NR15*, NR15*SO2, N=N, NR15*NR15*, NR15*C(R15*)2, NR15*C(R15*)2, C(R15*)2O, OC(R15*)2, G=C, CR15*=CR15*, Het, o Ar, con la condicion de que U* y V* no estén ausentes a la vez; W* es R'*R''N-, R'*R''*NR'*N-, R'*R''*NR'*NCO-, R'*2NR'*NC(=NR'*)-, R'*ONR'*C(=NR'*)-, o un grupo de formulas (4), W* es un grupo de formulas (5), Q* es NR'*, O o S; Ra* es H, alquilo C1-6, Ar-alquiloC0-6, Het-alquiloC0-6 o cicloalquilC3-6-alquiloC0-6, halogeno, OR1*, SR1*, COR1*, OH, N02, N(R1*)2, CO(NR1*)2, o CH2N(R1*)2; Rb* y Rc* se seleccionan independientemente entre el grupo que consiste en H, alquilo C1-6, Ar-alquiloC0-6, Het- alquiloC0-6 o cicloalquilC3-6-alquiloC0-6, halogeno, OR1*, SR1*, COR1*, OH, NO2, N(R1*)2, CO(NR1*)2, CH2N(R1*)2, o Rb* y Rc* se unen para formar un anillo aromático o no aromático de cinco o seis miembros, opcionalmente sustituido con halogeno, alquilo C1-4, OR1*, SR1*, COR1*, OH, NO2, N(R1*)2, CO(NR1*)2, CH2N(R1*)2, CN, o R''*R'*NC(=NR'*)-; X* es N=CR', C(O) u O; Y* está ausente, S u O; Z* es (CH2)t*, Het, Ar o cicloalquilo C3-7; M* es 1 o 2; N* es 0, 1, 2, o 3; q* es 0, 1, 2, o 3; r* es 0, 1 o 2; s* es 0, 1 o 2; t* es 0, 1 o 2; u* es 0, 1 o 2; v* es O o 1; y w* es 0 o 1; o una sal farmacéuticamente aceptable o un solvato del mismo. Formulacion correspondiente con 0,01 % a 50% p/p del compuesto de formula (1) o (2) y 5% a 99% de uno o más potenciadores de penetracion y ceras, pomadas o bases o combinaciones de las mismas, emolientes; antioxidantes y un tampon.Use of a vitronectin receptor antagonist for the preparation of a useful pharmaceutical formulation to inhibit excess scar formation on the skin of a mammal in need thereof by topical administration. Such skin has been cut, cracked, torn or injured during healing and excessive healing can be hypertrophic. Said antagonist is a compound of formula (1) or (2), wherein: R is H, C1-6 alkyl, Ar, Het or C1-6 alkylaryl; R1 is R7, A-C0-4 alkyl, A-C2-4 alkenyl, A-C2-4 alkynyl, A-C3-4 oxoalkenyl, A-C3-4 oxoalkynyl, C4-4-aminoalkyl or C3-4-aminoalkenyl 4, unsubstituted or substituted with any possible combination of one or more of R10 or R7; A is H, C3-6 cycloalkyl, Het or Ar; R7 is -COR8, -COCR'2R9, -C (S) R8, -S (O) mOR ', -S (O) mNR'R' ', -PO (OR'), -PO (OR ') 2 , -NO2, or tetrazolyl; each R8 is independently -OR ', -NR'R' '-NR'SO2R', -NR'OR 'or -OCR'2CO (O) R'; R9 is -OR ', -CN, -S (O) rR', -S (O) mN (R ') 2, -C (O) R', C (O) N (R) 2 or -CO2R ' ; R10 is H, halo, -OR11, -CN, -NR'R11, -NO2, -CF3, CF3S (O) r-, CO2R ', -CON (R') 2, A-alkylC0-6-, A- C1-6 oxoalkyl, A-C2-6- alkenyl, A-C2-6- alkynyl, A-C0-6- alkyloxy, A-C0-6- alkylamino or A-C0-6-S-alkyl (O) r-; R11 is R ', - C (O) R', -C (O) N (R ') 2, -C (O) OR', -S (O) mR 'or -S (O) mN (R') 2; R2 is a group of formulas (3), W is - (CHRg) a-U- (CHRg) b-; U is absent or is CO, CRg2, C (= CRg2), S (O) k, O, NRg, CRgORg, CRg (ORk) CRg2, CRg2CRg (ORk), C (O) CRg2, CRg2C (O), CONRi , NRiCO, OC (O), C (O) O, C (S) O, OC (S), C (S) NRg, NRgC (S), S (O) 2NRg, NRgS (O) 2, N = N, NRgNRg, NRgCRg2, CRg2NRg, CRg2O, OCRg2, C ::: C or CRg = CRg; G is NRe, S or O; Rg is H, C1-6 alkyl, Het-C0-6 alkyl, C3-7 cycloalkyl- C0-6 alkyl or Ar-C0-6 alkyl; Rk is Rg, -C (O) Rg, or -C (O) ORf; Ri is H, C1-6 alkyl, Het-C0-6 alkyl, C3-7 cycloalkyl, C0-6 alkyl, Ar-C0-6 alkyl or C1-6 alkyl substituted with one to three groups selected from the halogen-sewing group, CN, NRg2, ORg, SRg, CO2Rg, and CON (Rg) 2; Rf is H, C1-6 alkyl or Ar-C0-6 alkyl; Re is H, C1-6 alkyl, Ar-C0-6 alkyl, Het-C0-6 alkyl, C3-7 cycloalkyl-C0-6 alkyl or (CH2) kCO2Rg; Rb and Rc are independently selected from the group consisting of H, C1-6 alkyl, Ar-C0-6 alkyl, Het-C0-6 alkyl, C3-6 cycloalkyl-C0-6 alkyl, halogen, CF3, ORf, S (O) kRf , CORf, NO2, N (Rf) 2, CO (NRf) 2, and CH2N (Rf) 2, or Rb and Rc join to form a five or six-membered carbocyclic or heterocyclic, aromatic or non-aromatic ring, unsubstituted or substituted with up to three substituents selected from the group consisting of halogen, CF3, C1-4 alkyl, ORf, S (O) kRf, CORf, CO2Rf, OH, NO2, N (Rf) 2, CO (NRf) 2, CH2N (Rf) 2, and methylenedioxy; Q1, Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that no more than Q1, Q2, Q3 and Q4 is N; R 'is H, C1-6 alkyl, Ar-C0-6 alkyl or C3-6 cycloalkyl-C0-6 alkyl; R '' is R ', -C (O) R' or -C (O) OR '; R '' 'is H, C1-6 alkyl, Ar-C0-6 alkyl, Het-C0-6 alkyl, C3-6 cycloalkyl- halogen, CF3, ORf, S (O) kRf, CORf, NO2, N ( Rf) 2, CO (NRf) 2, or CH2N (Rf) 2; Ry is H, halo, -OR9, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S (O) r-, CO2Rg, -COR9 or -CONRg2, or C1-6 alkyl unsubstituted or substituted with halo , -ORg, -SRg, - CN, -NRgR '', -NO2, -CF3, R'S (O) r-, - CO2Rg, -CORg or -CONRg2; a is 0, 1 or 2; b is 0, 1 or 2; k is 0, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is 0, 1 or 2; u is 0 or 1; and v is 0 or 1; or a compound of formula (2), wherein A1 is C or N; E is a five- or six-membered heteroaromatic ring or a six-membered aromatic ring unsubstituted or substituted with R3 * or R4 *; X1-X2 is CHR1 * -CH, CR1 * = C, NR1 * -CH, S (O) or * -CH or O-CH; X3 is CR5 * R5 '*, NR5 *, S (O) or * or O; R * is H, C1-6 alkyl, Ar, Het, C1-6 alkylaryl; R '' * is R '*, -C (O) R' * or - C (O) OR5 *; R '' * is C1-6 alkyl, C3-7 cycloalkyl-C0-4 alkyl or Ar-C0-4 alkyl; R1 * is H, C1-6 alkyl, C3-7 cycloalkylC0-4alkyl or ArC0-4alkyl; R2 * is -OR '*, -NR' * R '' *, -NR '* SO2R' '' *, -NROR '*, -OC (R' *) 2C (O) OR '*, -OC ( R '*) 2OC (O) -R' *, - OC (R '*) 2C (O) N (R' *) 2, CF3 or COC (R '*) 2R2' *; R2 '* is -OR' *, -CN, -S (O) r * R '*, S (O) 2N (R' *) 2, -C (O) R '*, C (O) N ( R '*) 2 or -CO2R' *; R5 * and R5 '* are independently H, C1-6 alkyl, C3-7 cycloalkyl-C0-4 alkyl or Ar-C0-4 alkyl; R6 * is W- (C (R '*) 2) q * -Z * - (CR' * R10 *) r * -U * - (C (R '*) 2) s * -V * - or W '* - (C (R' *) 2) q * -U * - (C (R '*) 2) s * -; R3 *, R4 * and R7 * are independently H, halo, -OR12 *, -SR12 *. -CN, -NR '* R12 *, -NO2, -CF3, CF3S (O) r * -, -CO2R' *, -CON (R1 *) 2, R14 * -alkylC0-6-, R14 * -oxoalkylC1- 6, R14 * -C2- 6- alkenyl, R14 * -C2-6 alkynyl, R14 * -C0-6 -alkyloxy, R14 * -CalkylaminoC0-6 or R14 * -C0-6 -alkyl (O) r * -; R8 * is R '*, C (O) R' *, CN, NO2, SO2R '* or C (O) OR5 *; R9 * is R '*, -CF3, -SR' *, or -OR '*; R1O * is H, C1-4 alkyl, or -NR '* R' '*; R12 * is R '*, -C (O) R' *, - C (O) N (R '*) 2, -C (O) OR5 *, -S (O) m * R' * or S ( O) 2N (R '*) 2; R14 * is H, C3-6 cycloalkyl, Het or Ar; R15 * is H, C1-10 alkyl, C3-7 cycloalkyl-C0-8 alkyl or Ar-C0-8 alkyl; U * and V * are absent or are CO, C (R '*) 2, C = C (R15 *) 2, S (O) n *, O, NR15 *, CR15' * OR15 *, CR '* ( OR '' *) CR '* 2, CR' * 2CR '* (OR' '*), C (O) C (R' *) 2, C (R15 *) 2C (O), CONR15 *, NR15 * CO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR15 *, NR15 * C (S), SO2NR15 *, NR15 * SO2, N = N, NR15 * NR15 *, NR15 * C (R15 *) 2, NR15 * C (R15 *) 2, C (R15 *) 2O, OC (R15 *) 2, G = C, CR15 * = CR15 *, Het, or Ar , with the proviso that U * and V * are not absent at the same time; W * is R '* R''N-, R' * R '' * NR '* N-, R' * R '' * NR '* NCO-, R' * 2NR '* NC (= NR' * ) -, R '* ONR' * C (= NR '*) -, or a group of formulas (4), W * is a group of formulas (5), Q * is NR' *, O or S; Ra * is H, C1-6 alkyl, Ar-C0-6 alkyl, Het-C0-6 alkyl or C3-6 cycloalkyl, halogen, OR1 *, SR1 *, COR1 *, OH, N02, N (R1 *) 2, CO (NR1 *) 2, or CH2N (R1 *) 2; Rb * and Rc * are independently selected from the group consisting of H, C1-6 alkyl, Ar-C0-6 alkyl, Het-C0-6 alkyl or C3-6 cycloalkyl-halogen, OR1 *, SR1 *, COR1 *, OH, NO2, N (R1 *) 2, CO (NR1 *) 2, CH2N (R1 *) 2, or Rb * and Rc * join to form an aromatic or non-aromatic ring of five or six members, optionally halogen substituted, C1-4 alkyl, OR1 *, SR1 *, COR1 *, OH, NO2, N (R1 *) 2, CO (NR1 *) 2, CH2N (R1 *) 2, CN, or R '' * R '* NC (= NR' *) -; X * is N = CR ', C (O) or O; And * is absent, S or O; Z * is (CH2) t *, Het, Ar or C3-7 cycloalkyl; M * is 1 or 2; N * is 0, 1, 2, or 3; q * is 0, 1, 2, or 3; r * is 0, 1 or 2; s * is 0, 1 or 2; t * is 0, 1 or 2; u * is 0, 1 or 2; v * is O or 1; and w * is 0 or 1; or a pharmaceutically acceptable salt or solvate thereof. Corresponding formulation with 0.01% to 50% w / w of the compound of formula (1) or (2) and 5% to 99% of one or more penetration enhancers and waxes, ointments or bases or combinations thereof, emollients ; Antioxidants and a buffer.

ARP050105363A 2004-12-21 2005-12-20 USE OF A VITRONECTINE RECEIVER ANTAGONIST FOR THE PREPARATION OF A USEFUL PHARMACEUTICAL FORMULATION TO INHIBIT THE EXCESS OF SCARS FORMATION IN THE SKIN OF A MAMMER AND SUCH FORMULATION AR052823A1 (en)

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UA60311C2 (en) * 1996-10-02 2003-10-15 Смітклайн Бічам Корпорейшн Vitronectin receptor antagonists
UA71586C2 (en) * 1998-12-04 2004-12-15 Smithkline Beecham Corp A vitronectin receptor antagonist
WO2000046215A1 (en) * 1999-02-03 2000-08-10 Merck & Co., Inc. Benzazepine derivatives as alpha-v integrin receptor antagonists
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